Fueling Alzheimer’s Disease: Where Does Immunometabolism Stand?

Abstract

More than a century after the first description of Alzheimer’s disease (AD), the road to a cure for this complex and heterogeneous neurodegenerative disorder has been paved by countless descriptive hypotheses and successive clinical trial failures. Auspiciously, the era of genome-wide association studies revolutionized the classical “neurocentric” view of AD by providing clues that brain-resident immune cells (i.e., microglia and astrocytes) are also key players in the pathological and clinical trajectory of this neurodegenerative disorder. Considering that the intercommunication among neurons, astrocytes, and microglia is fundamental for the functional organization of the brain, it is evident that the disruption of the proper functioning of this “triad” could contribute to the neuroinflammatory and neurodegenerative events that occur in the AD brain. Importantly, recent scientific progress in the burgeoning field of immunometabolism, a crossroad between metabolism and immune response, shed light on the importance of metabolic reprogramming of brain-resident immune cells in AD pathology. In this sense, the present review is aimed to summarize and discuss the current knowledge on the metabolic patterns of brain-resident immune cells during the AD continuum, putting a special focus on glucose, amino acids, and lipid metabolism. Changing the “old” picture of AD pathological basis by integrating the role of brain-resident immune cells it is imperative to establish new and feasible therapeutic interventions able to curb neuroinflammatory and neurodegenerative processes, and consequently cognitive deterioration.

Keywords

Alzheimer’s disease amino acids astrocytes glucose lipids metabolism microglia

This paper is dedicated to the memory of Dr. Mark Smith. Despite his premature passing, Dr. Smith remains a reference in the field of Alzheimer’s disease research.

INTRODUCTION

The mammalian brain is an incredibly complex and highly energy-demanding organ comprising neurons, glial cells, and more than 1×10¹⁴ synapses. 1 The distinct cell populations of the brain work in a coordinated manner to fulfill several crucial functions, including electrical signaling, metabolic coupling, regulation of blood flow, axonal sheathing, and immune surveillance.2 –4 Over the last years, the long-standing notion of neurons as the structural and functional unit of the central nervous system (CNS) was challenged,5,6, 5,6 with exciting advances in the neuroscience field dethroning the old concept of glial cells as a mere glue for neurons. 7 Notably, glial cells greatly outnumber neurons throughout the CNS, reinforcing the physiological relevance of these cells. 8 Glia, particularly astrocytes and microglia, are very heterogeneous and dynamic cells and the principal orchestrators of neuroinflammation.9,10, 9,10 Recent breakthroughs in the promising field of immunometabolism suggest that structural and functional heterogeneity of microglia and astrocytes is strongly governed by distinct metabolic pathways in both health and disease.9,11, 9,11 Importantly, metabolic reprogramming in reactive glial cells not only fuels ongoing neuroinflammatory processes but also triggers neurodegeneration. 2 Within this scenario, aberrant activation of microglia and astrocytes has emerged as a major catalyst prime of a cascade of deleterious events that culminates in neuronal degeneration and demise in Alzheimer’s disease (AD).10,12, 10,12

Along with the aging of the population, AD has been recognized as the most prevailing age-related neurodegenerative disorder among elderly (≥65 years) and a growing epidemic across the globe. 13 According to the Global Burden of Disease database, it has been estimated that more than 44 million people worldwide are affected by AD or a related form of dementia, this figure being projected to triplicate by 2050.14,15, 14,15 Despite decades of massive research efforts, AD presently lacks a definitive cure, and most of the available treatments only address the symptoms of the disease. More than 200 anti-AD drugs have been tested in clinical trials, but only a few have received approval from the Food and Drug Administration with considerable controversy, 16 highlighting the need for a better understanding of the pathological root underlying AD.

The core clinical features of AD encompass a gradual memory impairment and cognitive decline that can be accompanied by perturbations in behavior, speech, visuospatial orientation, and motor system.17,18, 17,18 In the past, AD was defined as a clinical-pathologic entity, being diagnosed in life as possible or probable AD, and only confirmed postmortem with neuropathological identification of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs) being the gold standard for a definitive diagnosis of AD. 19 More recently, this paradigm shifted from a syndrome to a biological construct. In this sense, AD was conceptualized as a continuum that begins with a long asymptomatic or preclinical phase that gradually progresses to dementia.20 –24 Of note, during the preclinical phase, which precedes the clinically detectable dementia by decades (∼20 years), several pathophysiological processes coexist, triggering the disruption of brain structure and function. 25 AD manifests in two forms: sporadic and familial. The vast majority (∼95%) of AD cases are sporadic in origin and have age, the ɛ4 allele of the Apolipoprotein E gene (APOE4), and sex as the main risk factors. 26 In familial AD, mutant autosomal-dominant genes, including the genes for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), encode the major proteins involved in amyloid metabolism. 27

More than one century after the first case report, a daunting question persists: what causes the selective neuronal vulnerability in AD? There are various descriptive hypotheses regarding the causes of AD, the “Amyloid hypothesis” which states Aβ is the main culprit of AD onset, being the most prevailing and well-accepted by the scientific community. 28 However, this hypothesis fails to explain the pathological basis underlying sporadic AD cases. In the search for more pathological triggers of AD, neuroinflammation has emerged as a third core pathology in AD. Inappropriate and sustained activation of astrocytes and microglia has been shown to exacerbate Aβ and tau pathology. 29 Furthermore, a strong piece of evidence for a causal role for neuroinflammation in AD comes from genome-wide association studies (GWAS). In the hunt for genetic modifiers of AD, GWAS have uncovered that most of the genetic AD risk lies in genes closely related to immune response and highly expressed in microglia and astrocytes, such as APOE, and triggering receptor expressed on myeloid cells 2 (TREM2), among others30 –33, providing an unprecedented opportunity to better understand the pathobiology of AD. Notably, recent reports show a correlation between neuroinflammatory and immunometabolic pathways and Aβ and tau pathology.34,35, 34,35

Bearing in mind that the AD brain is characterized by energy crisis and chronic neuroinflammation, the first part of this review commences with an overview on the functional and phenotypic diversity of microglia and astrocytes during the different stages of the AD continuum. Drawing from extensive human and disease model data, the second part of this review is devoted to gather the latest evidence on the role of metabolic reprogramming of brain-resident immune cells during the pathological trajectory of AD, putting a focus on glucose, amino acids, and lipid metabolism. Lastly, the impact of sex as a biological variable on immunometabolic reprogramming in AD will be also discussed.

THE NEUROINFLAMMATORY FINGERPRINT IN ALZHEIMER’S DISEASE

Challenging the long-held “neurocentric” understanding of AD, clinical and preclinical research have recently attracted attention for the crucial role of neuroinflammation and glial cells during the pathological trajectory of this devastating neurodegenerative disease. By definition, neuroinflammation is a highly complex innate immune response of the CNS and a first line defense against certain pathogens and insults (e.g., misfolded proteins). Briefly, the activation of innate immunity initially occurs as a result of CNS cells sensing of two major “danger” signals, the pathogen-associated molecular patterns and the damage-associated molecular patterns via pattern-recognition receptors (PRRs). As the sensors of the innate immune system, PRRs not only regulate the activation of immune cells in response to these “danger” signals but also stimulate the release of inflammatory mediators. The main classes of PRRs comprise but are not restricted to Toll-like receptors, NOD-like receptors, and TREMs.36 –38 Importantly, astrocytes and microglia are the principal brain-resident immune cells that orchestrate innate immune response in the CNS. In a pathological context, microglia, astrocytes and neurons act in a synchronized manner to trigger neuronal degeneration and demise. 39 As aforementioned, neuroinflammation is an inexorable feature of AD pathology, being proposed that the inflammatory disease starts decades before the appearance of severe cognitive decay. 40

But what is the physiological role of the brain-resident immune cells? And how do they behave during the AD continuum? Microglia are the principal immune cells of the CNS and constitute ∼5–20% of total brain cells. Denominated as immune sentinels, microglia not only continuously survey the local milieu to “battle” against pathological insults but also perform multiple brain functions, including monitoring changes in neuronal activity, modulating learning and memory, and acting as local phagocytes and damage sensors in the brain parenchyma.41,42, 41,42 Microglia exist in two different states: “resting” and “activated”. Upon activation by a “danger” signal, microglia react changing their morphology from a ramified to an ameboid phenotype, dynamic motility behavior, gene expression profile, release of pro- and anti-inflammatory mediators and phagocytic ability. 43 Traditionally, two distinct and opposite phenotypes are identifiable for “activated microglia”, the pro-inflammatory M1 type and the neuroprotective M2 type. The M1 polarization can trigger inflammation and consequently cytotoxicity through the release of reactive oxygen species, nitrogen reactive species, pro-inflammatory cytokines, and chemokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. Additionally, M1 polarization is also marked by impaired release of neurotrophic factors and faulty phagocytic capacity. On the flipside, M2 polarization, which is responsible for the repairing and restoration of brain tissue homeostasis, is characterized by secretion of cytokines with anti-inflammatory activity such as IL-4, IL-10, growth factors (insulin-like growth factor, fibroblast growth factor), and neurotrophic growth factor (brain-derived neurotrophic factor, glial cell-derived neurotrophic factor). 44

Converging positron emission tomography (PET) studies have clearly shown that microglia activation and neuroinflammation are highly correlated with cognitive decline in AD individuals.45,46, 45,46 Importantly, increased microglial activation was detected in mild cognitive impairment (MCI) individuals, reinforcing the idea that neuroinflammation is an early event in the pathological trajectory of AD.45,47, 45,47 Using voxel-based biological parametric mapping, it was also confirmed that microglial activation is strongly correlated with both Aβ and tau pathology in MCI and AD individuals.48,49, 48,49 In the context of AD pathology, a handful of studies documented clusters of activated microglia in regions surrounding Aβ plaques and NFTs, being proposed that microglial activation contributes to the aberrant accumulation of the toxic proteins, and is not a merely epiphenomenon of their deposition.12,39, 12,39 Clinical and preclinical studies showed that microglial activation precedes and may drive tau spread over the neocortex following a Braak stage-like pattern.50 –52 Accumulating evidence revealed that phagocytosed tau within microglia can be secreted through exosomes, exacerbating tau pathology.53,54, 53,54 On the other hand, some studies also demonstrated that microglial activation per se can directly induce tau pathology.51,55, 51,55 Acting as a “danger” signal, Aβ can trigger microglial activation in AD56 –58 however, Aβ plaques and activated microglia only partially overlap topographically in the human brain,48,59, 48,59 and microglial activation can occur even before the appearance of Aβ plaque accumulation. That said, it has been argued that the co-occurrence of Aβ, tau and microglia abnormalities could function as a strong predictor of cognitive impairment in AD. 52

Importantly, microglia seem to play a double-edged sword role during AD trajectory, being discernible two peaks of microglia activation: a protective peak and a later pro-inflammatory peak.45,49,60 , 45,49,60 Briefly, a longitudinal neuroimaging study revealed that microglial activation appears at the asymptomatic stage of AD, favoring the phagocytosis and clearance of pathological protein aggregates and performing a neuroprotective role by secreting anti-inflammatory mediators and neurotrophic factors. In particular, it was demonstrated that activated microglia can form a barrier around Aβ plaques to prevent the formation of neurotoxic Aβ hotspots. 61 However, as disease progresses, protective microglia become ineffective, switching to a chronic pro-inflammatory phenotype with the consequent release of inflammatory cytokines, which, in turn, potentiate the deleterious inflammatory response and cause neuronal damage and demise.45,60, 45,60 Damage-associated molecular patterns, that arise from these processes, further activate microglia initiating a self-perpetuating pro-inflammatory cascade. 62 In advanced stages of the disease, the activation of microglia is accompanied by a defective phagocytic capacity due to a downregulation of Aβ phagocytic receptors, leading to a maladaptive immune response.39,63,64 , 39,63,64

Notably, the classical M1-M2 dichotomy was recently distraught by transcriptomic studies demonstrating that microglia can gradually change from a homeostatic state to several disease related phenotypes as AD progresses, 65 including disease-associated microglia (DAM), morphologically activated microglia (PAM), microglial neurodegenerative phenotype (MGnD), among other unidentified clusters.66,67, 66,67 Despite the exact role of the conversion of homeostatic microglia into these phenotypes during the AD progression remains largely elusive, several pieces of evidence unveil that DAM, MGnD, and PAM have distinct gene profiles and functions. First identified in the 5xFAD mouse model, DAM is characterized by a downregulation of homeostatic genes, whereas AD risk genes are upregulated. 66 Notably, microglia switch from homeostatic to DAM1 (TREM2-independent) and DAM2 (TREM2-dependent) stages following signals associated with AD pathology, such as Aβ accumulation. 66 In turn, MGnD is associated with the upregulation of a set of genes that favor phagocytosis and chemotaxis. 68 Lastly, it was found that the proportion of PAM is positively correlated with the occurrence of both Aβ and tau pathologies and the rate of cognitive decline. 69

Astrocytes, the most abundant type of glial cells, constitute approximately 20–40% of the total number of cells in the mammalian brain.70,71, 70,71 Structurally, astrocytes are distributed around blood vessels and neurons, connecting the periphery and the brain for energy exchange, thus acting as a bridge for communication between cells. 72 While astrocytes were initially thought to merely provide trophic support for neurons, it has been now recognized these glial cells are essential for brain homeostasis being involved in several physiological processes, including the uptake and recycling of neurotransmitters, modulation of synaptic activity, release of gliotransmitters, maintenance of the blood-brain barrier (BBB), ionic balance, brain energy metabolism, and neuroinflammation.73,74, 73,74 Classically depicted as star-like cells, astrocytes are a heterogenous group of brain cells with different structural and functional characteristics.75,76, 75,76 Under pathological conditions, astrocytes switch to a reactive state that is accompanied by morphological, molecular, and functional changes.77,78, 77,78 Similarly to microglia, reactive astrocytes can be categorized in two polarization states, the neurotoxic or pro-inflammatory phenotype (A1) and the neuroprotective or anti-inflammatory phenotype (A2).71,79, 71,79 However, it is important to have in mind that this simple dichotomy of the A1/A2 phenotypes does not reflect the wide range of astrocytic phenotypes but facilitates the interpretation of the reactive state of astrocytes in several neurodegenerative conditions.80,81, 80,81 Back to 1910, Alois Alzheimer described the presence of astrocytes hypertrophy in the vicinity of Aβ plaques, being now recognized that astrogliosis is a prominent pathological feature in the AD brain.82 –84 Postmortem studies showed a marked increase in glial fibrillary acidic protein (GFAP), the main constituent of astrocytes intermediate filaments and a proxy of astrocyte reactivity, in individuals at pre-clinical stages of AD. 85 Consistently, recent findings revealed that plasma levels of GFAP are associated with brain Aβ status and the onset of cognitive decline in AD, being proposed as a promising biomarker in the diagnosis of the prodromic stages of AD.86,87, 86,87 The early appearance of astrocyte reactivity along AD trajectory was further confirmed by subsequent neuroimaging studies using PET tracers that bind to the reactive astrocyte marker monoamine oxidase B, including [¹⁸F]THK-5351 and ¹¹C-deuterium-L-deprenyl (¹¹C-DED).88,89, 88,89 Importantly, preclinical evidence suggests that astrocyte reactivity is critical for triggering Aβ-induced tau phosphorylation 90 and that the attenuation of astrocyte reactivity mitigates tau pathology.91,92, 91,92 Furthermore, GFAP-positive astrocytes were shown to be able to internalize tau and may contribute to its propagation.93,94, 93,94 Indeed, following internalization, astrocytes can degrade the internalized tau or release it to the extracellular space, propagating the pathological tau to healthy neurons. 95 Lastly, it was recently posited that the neurotoxic reactive astrocytes are induced by activated microglia. Activated microglia induce A1 astrocytes by secreting Il-1α, TNF, and C1q, these cytokines being necessary and sufficient to induce A1 astrocytes. In this sense, A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons. 79 In line with this, it was demonstrated that the selective pharmacological inhibition of Aβ-induced microglial activation can block reactive astrocyte conversion, sparing neurons. 96 Considering that physical and chemical interactions between endothelial cells and astrocytes are required to maintain BBB integrity, a recent study from Polimio and colleagues 97 also revealed that early changes in astrocytes morphology during AD trajectory underlie the loss of direct astrocyte-endothelium contact in the hippocampus, contributing to the establishment of vascular pathology in AD.

Overall, during the last decades, it has become clear that microglia and astrocytes are major contributors to the inflammatory and neurodegenerative processes that occur in the AD brain, and not simple bystanders as originally thought.

WHAT IS THE ROLE OF IMMUNOMETABOLISM IN ALZHEIMER’S DISEASE?

The brain, one of the most energy-consuming organs in the mammalian body, critically relies on the tight regulatory mechanisms that ensure the adequate spatial and temporal delivery of energy substrates to sustain normal functioning. Despite comprising ∼2% of the body mass, the brain consumes ∼20% of energy substrates at rest, mainly to fulfill high demand physiological tasks such as maintenance and restoration of neuronal ion gradients, synaptic transmission, and recycling of neurotransmitters.98 –100 In the adult brain, glucose is the long-established, obligatory fuel to provide energy in the form of adenosine triphosphate (ATP) via two main metabolic routes, glycolysis and oxidative phosphorylation (OXPHOS). However, under certain circumstances, the brain has the capacity of using other energy substrates, including lactate, ketone bodies, and lipids. 101 Of note, remarkable advances in the neuroscience field revealed that the metabolic status of the brain is, in part, dictated by the interplay between neurons and glial cells (i.e., astrocytes and microglia).102,103, 102,103

Over the past 2 decades, the area of immunometabolism made great strides to unveil the crucial role of metabolic reprogramming on the pathological fate of brain-resident immune cells in AD. 104 Interestingly, immune cells depend on the rapid metabolic reprogramming to supply sufficient ATP to react to pathogenic or environmental dangers, whereas inflammatory cytokines secreted by immune cells are also able to modulate cellular metabolism, suggesting a reciprocal relation between metabolism and the function of immune cells.9,11,105 , 9,11,105

Considering that AD is characterized by a progressive deterioration of brain energy metabolism, the upcoming sub-sections are devoted to highlight how AD-related metabolic alterations impact the function of astrocytes and microglia, and vice-versa.

Glucose metabolism

In a clear and concise manner, glucose metabolism can have different fates originating numerous biomolecules and being heavily dependent on certain solute carrier transporters, namely glucose transporters (GLUTs) and monocarboxylate transporters (MCTs). 106 Briefly, glucose is sensed and transported inside the cells through GLUTs and in an initial step is phosphorylated by hexokinase (HK) to produce glucose-6-phosphate (Glc-6-P). Glc-6-P can be processed into three main metabolic routes: 1) glycolysis, with the consequent production of pyruvate, ATP and NADH. In turn, pyruvate reaches mitochondria, where it is metabolized through the tricarboxylic acid (TCA) cycle and OXPHOS, producing ATP and CO₂. Glycolytic and TCA cycle intermediates are also used for the synthesis of amino acids and neurotransmitters. Alternatively, pyruvate can be reduced to lactate by the action of the lactate dehydrogenase (LDH). 2) Glc-6-P can be metabolized through the pentose phosphate pathway, providing pentose for nucleotide synthesis and NADPH required, for instance, in the synthesis of lipids. 3) Lastly, Glc-6-P is a precursor for glycogen, in astrocytes.107,108, 107,108

As abovementioned, astrocytes and microglia are key regulators of brain energy metabolism.9,102,109 , 9,102,109 From the standpoint of glucose metabolism, neurons and astrocytes possess distinct metabolic profiles. Shortly, in the presence of oxygen, astrocytes are predominantly glycolytic producing pyruvate and lactate, while neurons preferentially metabolize glucose via OXPHOS to generate ATP.73,110, 73,110 Astrocytes provide metabolic support to neurons by sensing and carrying circulating glucose, being both GLUT1 and GLUT2 essential for this astrocytic function. 111 Glycolytic enzymes are also highly expressed in astrocytes with approximately 80% of the glucose being metabolized through glycolysis. Neurons mostly express the high-affinity glucose sensor GLUT3 but present a low level of glycolysis due to the rapid degradation of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, isoform 3 (PFKFB3), a rate-limiting enzyme of glycolysis.112,113, 112,113 Furthermore, astrocytes also express lactate dehydrogenase 5 (LDH5), which favors the conversion of pyruvate into lactate, while neurons exclusively express lactate dehydrogenase 1 (LDH1) that catalyzes conversion of lactate into pyruvate. 114 Because of their constant “patrolling” function, microglia possess huge demand for ATP. The functional polarization of microglia and consequent response to neuroinflammation are dictated by changes in the metabolic signature of these immune cells.115,116, 115,116 Microglia are equipped with efficient machinery for processing of a variety of biomolecules including glucose, ketone bodies, amino acids and free fatty acids (FFAs), 117 indicating a flexible use of available energy resources. However, the main energy substrate for microglia is glucose, which enters the cell through different GLUTs,118,119, 118,119 being GLUT1, GLUT3, and GLUT5 the major isoforms.120,121, 120,121 A comprehensive transcriptome profiling of genes associated with energy metabolism revealed that microglia express the set of genes required for both glycolytic and OXPHOS 122 , with the microglial bioenergetic phenotype being dependent on the activation state.123,124, 123,124 Resting microglia are believed to primarily rely on OXPHOS for ATP production,125 –127 whereas activated microglia display a metabolic switch phenotype from OXPHOS to glycolysis as mirrored by increased lactate production and decreased mitochondrial oxygen consumption.128,129, 128,129 In agreement, a single-cell sequencing analysis showed that glycolytic genes are upregulated in proinflammatory human microglia. 130

Recognized as a metabolic disease, brain glucose hypometabolism has been described to appear early in the genesis of AD pathology, even before the onset of clinically measurable symptoms.131,132, 131,132 Converging PET imaging studies using the 18 F-fluorodeoxyglucose (FDG) tracer, consistently reported decreased regional activity-dependent glucose uptake and utilization during the different stages of the AD continuum. Particularly, these decreases are primarily observed in the parieto-temporal and posterior cingulate cortices during the early stages and propagated to the frontal areas as disease advances.133 –135 Notably, FDG-PET has emerged as a powerful tool to predict MCI-to-AD conversion with high precision.136,137, 136,137 So, the first question that emanates in the immunometabolism picture is: what is the contribution of brain-resident immune cells to faulty glucose metabolism in AD? A recent longitudinal study established a causal relation between the decline in astrocytes function, measured by ¹¹C-deuterium-L-deprenyl binding, and the decrease in brain glucose metabolism in AD individuals, attributing a pathological role to these glial cells in brain glucose hypometabolism. 138 The relationship between microglia activity and glucose metabolism in AD was also delved through the combination of FDG-PET and [¹¹C]-(R)-PK11195 imaging, which measures of microglial activation associated with mitochondrial overexpression of the 18 kDa translocator protein (TSPO). 139 This study disclosed a significant and widespread microglial activation in AD individuals, which had a spatial concordance with brain glucose hypometabolism, mainly in AD-signature regions, i.e., the temporo-parietal cortices, but involving also the frontal and occipital regions. 139 Mechanistically, studies in postmortem brain tissue detected that defective glucose metabolism in AD is associated with a drastic reduction in glucose transport associated with diminished astrocytic GLUT1 and neuronal GLUT3 expression.140 –142 Likewise, experimental data derived from the transgenic arctic Aβ (arcAβ) mouse model also unveil a reduction in astrocytic GLUT1 as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, which preceded a widespread Aβ plaque pathology. 143 Noticeably, in the hippocampus, a key brain structure affected in AD, the transport and metabolism of glucose are faster in astrocytes than in neurons, 144 which reinforce the great involvement of these glial cells on defective glucose metabolism in AD pathology. Furthermore, previous studies detected that abnormal aerobic glycolysis in astrocytes is a primary and dominant event during the early stages of AD.145,146, 145,146

Predictable, being at the hub of glucose metabolism, structural and functional mitochondrial disturbances have been extensively described along the AD continuum.147,148, 147,148 Particularly, TCA cycle arrest is strongly associated with AD. Back to 2009, Bubber and colleagues 149 reported that impaired activity of pyruvate, isocitrate and α-ketoglutarate dehydrogenases is strongly correlated with the clinical state of AD, establishing a causal relation between the progressive decay of mitochondrial functioning with AD severity. Consistently, a recent transcriptomic study shows a downregulation on TCA cycle genes in both AD brain tissue and peripheral blood cells, with pyruvate dehydrogenase complex subunit, succinyl-CoA synthetase subunit, and malate dehydrogenase subunit emerging as candidate biomarkers for the early diagnosis of this devastating neurodegenerative disease. 150 Deterioration of mitochondrial bioenergetics function in AD is also manifested by distresses in several components of the OXPHOS, being the reduction in cytochrome c oxidase activity the most congruent defect documented in both clinical and preclinical studies.151 –155 Interestingly, another contemporary transcriptomic analysis of astrocytes in AD patients confirmed that the downregulation of nuclear-encoded mitochondrial genes of the TCA cycle and OXPHOS components is inversely correlated with the disease stages defined by Braak scoring, suggesting that early and progressive malfunction of astrocytic mitochondria contribute to AD. 156 In the context of AD pathology, the disruption of microglial glucose metabolism is characterized by a metabolic shift towards glycolysis and impaired mitochondrial OXPHOS. 157 Recent breakthroughs revealed that during the early stages of AD, activated microglia exhibited increased glucose consumption. However, the late stages are marked by a metabolic reprogramming breakdown as denoted by impaired glucose uptake capacity and mitochondrial function.158,159, 158,159 In detail, preclinical research detected increased expression of glycolytic enzymes and glycolysis rate in microglial cells from APP/PS1 mouse model.35,160, 35,160 In line with this finding, microglia from 6-month-old 3xTgAD mice had a considerable increase in glycolysis rate. However, this effect is age-dependent as the glycolysis in 18-month-old 3xTgAD mice returns to the control levels. 161 Taking advantage of the 5xFAD mouse model, FDG-PET and FDG uptake studies revealed a noticeable increase in glucose uptake in hippocampal microglia. 162 Remarkably, scRNA-seq data showed that changes in glucose metabolism signature including glucose transporters, glycolysis and OXPHOS, mainly occurred in microglia in this preclinical model. That said, this data suggests a reconfiguration of microglial glucose metabolism in the hippocampus during the course of AD pathology. 162

Searching for a “culprit” of ineffective microglial function in AD, exciting preclinical data demonstrated that acute exposure to the “danger” signal Aβ can favor microglial glycolysis, phagocytosis and chemotaxis, while chronic exposure triggers metabolic dysregulation and compromised immune functions.34,158,163 , 34,158,163 Mechanistically, it was demonstrated that Aβ induces metabolic reprogramming of microglia from mitochondrial OXPHOS to glycolysis via mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1α pathway, impairing the defensive functions of microglia. 158 Furthermore, it has been hypothesized that microglial mitochondrial impairment may result from the activation of microglial ATP receptors. 164 Additionally, pharmacological and genetic approaches revealed that the mitochondrial translocator TSPO is required for the preservation of energy supply and clustering of phagocytic microglia around Aβ plaques.165,166, 165,166 Importantly, glucose metabolic reprogramming in microglia may have an important translational implication. A comparative study using postmortem brain tissue from AD individuals and brains from the 5xFAD mouse model revealed a substantial increment in the microglial levels of HK2, an enzyme that supports inflammatory responses by rapidly increasing glycolysis. 167 Interestingly, it was recently proposed that mitochondrial TSPO and HK2 act in a coordinated manner to control the glycolytic-OXPHOS metabolic balance and phagocytosis in microglia. 165 From a therapeutic perspective, targeting HK2 was shown to significantly promote microglial phagocytosis, reduce Aβ burden and attenuate cognitive decline in the 5xFAD mouse model.167,168, 167,168 Remarkably, Aβ and tau can also indirectly modulate glucose metabolism by up-regulating cytokines and pro-inflammatory reactions related to the M1 phenotype through IL-1β and Interferon gamma (IFNγ) signaling pathways. Inflammatory cytokines trigger glycolysis associated with disruption of the TCA cycle and uncoupling of OXPHOS.34,129,169 , 34,129,169

Studies addressing the role of the dynamic aspect of mitochondrial biology during chronic activation of brain-resident immune cells in AD are scarce. However, pioneering studies developed in AD mouse models indicate that activated microglia exhibit mitochondrial damage due to perturbations in mitochondrial dynamics. 170 Considering that microglial phagocytosis and Aβ clearance heavily rely on “mitochondrial health”, it has been proposed that the restoration of mitochondrial function and mitophagy in microglia may represent a neuroprotective strategy that curbs neuroinflammation. 171 Notably, Fang and colleagues 172 detected an increase in the number of damaged mitochondria and a drastic reduction (∼60%) in mitophagy in APP/PS1 mice when compared with the respective wild-type mice. Surprisingly, the treatment of APP/PS1 with the mitophagy inducers urolithin A or actinonin decreased the number of damaged mitochondria and increased mitophagy rate and Aβ phagocytosis, these alterations being accompanied by a reduction in microglia number and lengths of processes indicating a phenotypic shift towards phagocytic morphology. 172 Additionally, the levels of proinflammatory cytokines IL-6 and TNF-α were also reduced in APP/PS1 mice treated with mitophagy inducers. 172

In the immunometabolism field, geneticists have also turned their focus to the role of AD risk gene APOE4. In humans, there are three predominant APOE alleles: ɛ2 (APOE2), ɛ3 (APOE3), and ɛ4 (APOE4) alleles, which confer contrasting levels of disease risk. Indeed, the APOE4 allele has the highest risk for developing AD,173,174, 173,174 while APOE2 and APOE3 alleles are neuroprotective. 175 Interestingly, APOE4 is a genetic risk factor for AD in a gene dose-dependent manner, since heterozygous and homozygous have a 2-3-fold and 12-fold increased risk of developing AD, respectively. 176 State-of-the-art research firmly posits that brain hypometabolism is unequivocally linked to APOE4.177,178, 177,178 Indeed, clear-cut experimental evidence indicates that APOE4 expression is associated with a reduction in cerebral glucose uptake as well as decreased expression of metabolic genes.179 –181 At the cellular level, APOE4 was shown to impact astrocytes metabolism as reflected by increased glucose flux through pentose phosphate pathway, in both re-entry into glycolysis (gluconeogenesis), and increased lactate synthesis, with a less oxidative TCA cycle. 181

Regarding astrocyte-neuron metabolic coupling, lactate emerged as a key molecule. Indeed, it has been proposed that lactate, a glucose metabolite, is produced in astrocytes and subsequently shuttled to neurons as an energy substrate. 182 Lactate levels are higher in astrocytes than in neurons, thus lactate needs to be transported from astrocytes to neurons via the MCT to maintain the dynamic balance of lactate metabolism and regulate long-term memory.183 –186 There are different types of MCTs that have different affinities for lactate. For instance, astrocytes express lower-affinity MCT1 and MCT4, while neurons exclusively express high-affinity MCT2. 187 That said, lactate is not merely a metabolic waste product, but a vital energy molecule produced by astrocytes. Lactate levels have been documented to be increased in the cerebrospinal fluid (CSF) of AD individuals.188,189, 188,189 Interestingly, a recent study confirmed the higher CSF lactate concentration in AD individuals; however, the higher lactate levels were detected in AD individuals with less severe cognitive impairment. 190 In a step further, Hirata and colleagues 191 examined the alterations in brain lactate levels and their association with astrocytic activities in AD. Taking advantage of magnetic resonance spectroscopy, these authors detected a significant increase in lactate levels in the posterior cingulate cortex of AD individuals, a region that has been identified as one of the most implicated areas in energy metabolism changes in AD. Of note, high lactate levels were accompanied by increased levels of myo-inositol, an astrocytic marker, which suggests that impaired lactate shuttle of reactive astrocytes may disrupt energy regulation, resulting in surplus lactate levels in AD. 191 Remarkably, lactate can also act as a signaling molecule by inducing histone lactylation, and consequently preserving brain homeostasis.112,192–194 , 112,192–194 Under this premise, Pan and colleagues 195 firstly observed elevated histone lactylation in brain samples from both 5xFAD mice and AD individuals, discovering a lactate-dependent histone modification, histone 4 lysine 12 (H4K12la). Increased glycolytic activity in microglia surrounding Aβ-plaques in 5xFAD mice was shown to be mediated by histone lactylation, which enhances the transcription of glycolytic genes. 195 In this sense, these authors proposed that microglial metabolic reprogramming towards glycolysis may constitute a vicious feedback loop, whereby enhanced lactate production due to high glycolysis rate promotes the transcription of glycolytic genes, leading to an imbalance in microglia homeostasis and potentiating neuroinflammation and AD pathological phenotype. 195 Importantly, the interruption of this loop with the microglia-specific ablation of pyruvate kinase M2 (PKM2), a rate-limiting glycolytic enzyme, was shown to ameliorate microglial dysfunction, Aβ pathology and cognitive function. 195 In a step further, recent breakthroughs revealed that PKM2 also plays a critical role in the transition of microglia from a homeostatic to DAM1 stage. 196 Indeed, it was found that microglia from 5xFAD mice without PKM2 exhibit a robust increase in DAM1 markers in a distinct metabolic cluster characterized by an enrichment in genes involved in glucose metabolism, and consequently, increased glycolysis and spare respiratory capacity and restoration of mitochondrial cristae. 196 Overall, these findings further highlight the crucial contribution of glucose dyshomeostasis to the development of DAM signature in AD.

To summarize, this piece of evidence underscores the contribution of the metabolic reprogramming of both microglia and astrocytes to the characteristic brain glucose hypometabolism documented along the AD spectrum, which may be meaningful for innovative translational drug discoveries for this neurodegenerative disorder.

Amino acids metabolism

Aside from the well-known function as basic units of proteins, amino acids can also act as neurotransmitters and metabolic intermediates in multiple pathways. Importantly, amino acids metabolism has been shown to influence the neuroinflammatory response by rewiring the metabolic switches and controlling the redox balance during the activation of the immune cells. 197 At the brain level, branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine are crucial not only for energy production but also for the compartmentalization and synthesis of glutamate, the main excitatory neurotransmitter.198,199, 198,199 Glutamate is synthesized from the TCA cycle intermediate α-ketoglutarate that provides the carbon backbone, 200 while the amino group is derived from nitrogen donors such as BCAAs. 198 Succinctly, the first step of BCAAs metabolism is the reversible transamination catalyzed by the branched-chain amino acid transaminase (BCAT) producing the corresponding branched-chain α-keto acids (BCKAs) and glutamate. Subsequently, the BCKAs suffer an irreversible oxidative decarboxylation catalyzed by the branched-chain alpha-ketoacid dehydrogenase complex, followed by multiple reactions, ultimately yielding acetyl-CoA and succinyl-CoA, which can be incorporated in the TCA cycle serving as supplementary energy substrates for brain cells.99,201, 99,201 Only a small fraction of glutamate from the circulating peripheral blood crosses the BBB, thus de novo synthesis is obligatory to maintain brain glutamate pool. 199 Synaptic glutamate released from neurons is “captured” by the surrounding astrocytes and converted into glutamine by the action of the enzyme glutamine synthetase, which is expressed exclusively in astrocytes.202,203, 202,203 In turn, glutamine is released into the extracellular space and taken up into GABAergic and glutamatergic neurons. Once inside the neurons, glutamine serves as a substrate for the mitochondrial enzyme phosphate-activated glutaminase, which is essential to replenish the neuronal glutamate pool. 202 This exchange of metabolites between neurons and astrocytes is denominated by glutamate-glutamine cycle, 204 being this cycle intertwined with the availability of glucose to the brain since the conversion of glutamate to glutamine by glutamine synthetase requires ATP. 205

Lessons from clinical and preclinical studies unveil that disturbances in BCAAs metabolism are involved in the pathophysiology of AD.206 –208 In a prospective study of eight cohorts, metabolomic analysis revealed that lower levels of circulating BCAAs were associated with an increased risk of dementia and AD. 209 Similarly, several studies documented a drastic reduction in valine levels in the CSF and plasma of AD individuals.210 –212 By Mendelian randomization, Larsson and Markus 213 revealed that a genetic predisposition to higher plasma isoleucine levels was positively associated with AD. Additionally, an increment of 28% in the expression of cytosolic BCAT was detected in the hippocampus of AD individuals, when compared with the respective controls. 214

Postmortem evidence from AD individuals and functional studies in animal models of the disease has extensively highlighted the involvement of dysfunctional glutamatergic neurons and circuits in AD, in part, due to glutamate toxicity.215,216, 215,216 However, there are controversial findings regarding the changes in glutamate levels during the pathological course of AD. For instance, a handful of studies reported high levels of glutamate in the CSF of AD individuals when compared with MCI individuals and controls.217 –220 Other studies revealed decreased or unchanged glutamate levels in AD individuals.221 –224 Considering that BCAAs metabolism dictates the fate of glutamate, a recent functional study was undertaken to fill some gaps in the field. By mapping BCAAs metabolism, Salcedo and collaborators 225 found reduced amino acids synthesis of glutamate, glutamine, and aspartate derived from leucine metabolism in familial AD human induced pluripotent stem cell (hiPSC)-derived astrocytes when compared with the control astrocytes. Importantly, these authors suggest that this impairment in astrocytic BCAAs metabolism may contribute to neurotransmitter and energetic imbalances in the AD brain. 225 Recent breakthroughs from the same research group also revealed higher rates of glycolysis and glucose oxidative metabolism in familial AD hiPSC-derived astrocytes, accompanied by an elevated glutamate synthesis. 226 In light of these results, it was speculated that a hypermetabolic phenotype in astrocytes during the early phases of AD pathophysiology is linked to a toxic accumulation of glutamate. To our knowledge the role of BCAA metabolism in AD microglia remains unexplored.

Lipid metabolism

Brain health and function is closely tied to lipid metabolism. This is not surprising considering that the brain is the second “fattiest” tissue in the body, with the lipid content representing approximately 50–60% of its dry weight.227,228, 227,228 Lipids are a structurally diverse group of molecules that have FFAs as the main building blocks. 229 Brain lipid content generally comprises cholesterol, phospholipids, and sphingolipids.230 –232 Once regarded merely as key components of cellular membranes, including synapses and myelin sheath, it has been now recognized that lipids have also a center stage on cell signaling by acting as signaling molecules and in some circumstances, lipids can also serve as bioenergetic fuels. 233 Of note, it is estimated that nearly 20% of the total energy consumption of the adult brain resulted from the β-oxidation of FFAs, which occurs entirely in astrocytes.234,235, 234,235 Paradoxically, under conditions of FFAs surplus, the brain has the capacity of storing FFAs in the form of lipid droplets (LDs). 236 Perceived as mere cytoplasmic inclusions of fat for a long time, LDs have emerged in recent years as evolutionarily conserved organelles that dynamically stockpile FFAs, being recognized as central hubs for lipid metabolism.237,238, 237,238 LDs have a unique architecture comprising a hydrophobic core of neutral lipids, including triglycerides and cholesterol esters, enclosed by a protein-decorated phospholipid monolayer. 239 But what is the physiological importance of storing FFAs in LDs? First and foremost, the storage of lipids in LDs circumvents lipotoxicity, 240 endoplasmic reticulum stress 241 and mitochondrial damage by blocking the buildup of cytosolic FFAs, which can be toxic. 242 Secondly, during periods of nutrient depletion and stress, this storage provides a specialized conduit for the timely delivery of FFAs into the mitochondria as an alternative fuel source. 243 Interestingly, neurons do not naturally present LDs and spurn FFAs for energizing oxidative ATP synthesis. 244 However, LDs can be observed in neurons as a consequence of ageing and stressful conditions involving redox imbalance and lipotoxicity. 245

The first clue for the involvement of lipid dysmetabolism in AD was provided in 1907 with the first case report of AD. At that time, besides the notorious Aβ deposition and tau aggregates, Alois Alzheimer also described the presence of several glial cells containing “adipose saccules”. 246 Succeeding lipidomic and metabolomic studies have consistently reported fluctuations in the levels of various lipid classes at different stages of the AD continuum. 247 For instance, alterations in circulating phospholipid levels have been linked to cognitive deterioration in AD individuals, 248 with profound changes in sphingomyelin and ceramide levels being reported during the initial stages of the disease. 249 Consistently, a marked increase in ceramide levels was also documented during the early stages of AD, particularly in the frontal and temporal cortices.250 –252 Of note, this increase in ceramide levels is accompanied by a reduction in sphingomyelin levels,253,254, 253,254 suggesting a shift in lipid metabolism towards ceramide accumulation. Accordingly, it was found that these alterations in ceramide and sphingomyelin are associated with an upregulation of genes involved in ceramide de novo synthesis and sphingomyelin degradation and downregulation of genes that regulate sphingomyelin synthesis. 255 Across several lipidomic studies in postmortem brain tissue from MCI and AD individuals, reduced levels of glycerophospholipids (i.e., phosphatidylcholines, phosphatidylinositols, and phosphatidylethanolamines) were also observed, particularly in vulnerable regions such as cerebral cortex and hippocampus.256 –259 Moreover, increased circulating and brain cholesterol levels have been extensively reported in MCI and AD individuals,250,260–262 , 250,260–262 being established a positive correlation between brain cholesterol levels and the severity of AD. 250 Importantly, an exciting study from Mori and colleagues found an abnormal accumulation of cholesterol in cores of mature senile plaques in the brain of AD individuals and APP transgenic mice, 263 providing the first hint for an involvement of cholesterol in the amyloidogenic processing of AβPP and formation of senile plaques. Nowadays, cholesterol is conjectured as a modulator of the amyloid cascade since the Aβ generation and aggregation occurs at cholesterol-rich membrane microdomains termed “lipid rafts”. 264

The involvement of lipid metabolism in AD is further strengthened by recent GWAS studies that identified several genes related to lipid homeostasis, including APOE, as major risk factors for both sporadic and inherited familial AD. 265 Later, two contemporary meta-analyses corroborated that genes implicated in lipid processing and immunoregulation are associated with the onset of AD.32,266, 32,266 In the brain, ApoE is the main cholesterol carrier involved in lipid metabolism, 267 being primarily synthesized by astrocytes and microglia with the purpose of controlling the delivery of lipids to neurons which are required for the maintenance of structural integrity and damage repair.268 –272 However, under stress conditions, neurons can also express ApoE. 273 On the path of demystifying the pathological root underlying AD pathology, recent breakthroughs deconstructed the impact of APOE4 on lipid metabolism in both microglia and astrocytes. Within this context, human iPSCs-derived glial cells have been used as a powerful tool to model familial and sporadic AD cellular pathogenesis. In iPSCs-derived microglia, it was found that APOE4 induces a lipid-accumulated state due to a decreased uptake of extracellular FFAs and lipoproteins, impairing microglial surveillance of neuronal-network activity. 274 Accordingly, challenging iPSCs-derived microglia with fibrillar Aβ was shown to induce the expression of acyl-CoA synthetase 1 (ACSL1), a key regulator of LDs biogenesis, triglyceride synthesis and LDs accumulation in an ApoE4-dependent manner. 275 Importantly, ApoE4-triggered LDs accumulation in microglia is correlated with a proinflammatory state.274,275, 274,275 Furthermore, conditioned media from LDs-containing microglia was shown to trigger tau phosphorylation and neurotoxicity in an ApoE4-dependent manner. 275 Conversely, the pharmacological inhibition of ACSL1 reduces the intracellular LDs content in ApoE4-expressing iPSCs-derived microglia and sustains the homeostatic states of microglia to support neuronal networks. 275 Similarly, using the P301S tauopathy mouse model, APOE4 was found to contribute to LDs accumulation and altered cholesterol metabolism, exacerbating microglia-mediated, tau-dependent neurodegeneration. 276 ApoE4-expressing iPSCs-derived astrocytes were also shown to exhibit a disease-relevant phenotype as mirrored in disrupted intracellular cholesterol/lipid homeostasis, increased inflammatory signature, and reduced Aβ uptake. 277 These findings were corroborated by a study from Sienski and colleagues 278 documenting an increase in unsaturation of FFAs and LDs accumulation in ApoE4-expressing human iPSC-derived astrocytes, which can be reversed by the supplementation of culture medium with choline, a soluble phospholipid precursor. Furthermore, recent scientific progress revealed that APOE4 can also impair astrocytes-neuron coupling of FFAs metabolism. 279 In detail, it was found that APOE4 impairs the transfer of FFAs from neuronal LDs and their posterior internalization by astrocytes. 279 Furthermore, APOE4 triggers a metabolic shift towards enhanced glucose metabolism and reduced fatty acid β-oxidation, which subsequently elicits lipid accumulation in astrocytes. 279 Altogether, these alterations ultimately lead to a compromised metabolic and synaptic support to neurons. Alternatively, it was also demonstrated that neuronal lipid synthesis and LDS accumulation in astrocytes are driven by a lactate shuttle via ApoE. Briefly, lactate transferred from astrocytes to neurons is used for lipid synthesis, which in turn are transported back to astrocytes through FAs transport proteins and apolipoproteins. 280 However, the expression of ApoE4 impairs the lipid efflux between neurons and astrocytes, which in turn promotes LDs accumulation and neuronal demise. 280

Besides APOE4, TREM2, a pattern recognition receptor abundantly expressed on microglia, also constitutes a risk factor for developing AD. 281 TREM2 has been a major focus of the neuroscience community after recent studies revealed that variants of this gene markedly increase the risk of AD, particularly the R47H variant.30,282,283 , 30,282,283 TREM2 deficiency has been shown to disrupt the formation of the neuroprotective “microglia barrier” that regulates Aβ compaction and insulation. 284 Recently denominated as a modulator of lipid metabolism in microglia, 285 TREM2 was previously shown to maintain microglial metabolic fitness in AD through mTOR signaling pathway. 286 To expand the knowledge regarding the influence of TREM2 in metabolic status, Nugent and colleagues 287 demonstrated that wild-type microglia acquire a disease-associated transcriptional state upon a chronic myelin phagocytic challenge, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. Specifically, TREM2-deficient microglia fail to clear myelin cholesterol, resulting in cholesteryl ester accumulation. The pathological relevance of cholesteryl esters in AD pathology was previously highlighted in a comparative lipidomic study revealing its accumulation in the brain of AD individuals and APP/PS1 mice. 288 Within this scenario, it was proposed that TREM2 is a key transcriptional regulator of cholesterol transport and metabolism as TREM2 loss-of-function triggers a pathogenic accumulation of lipids in microglia. 287 Having in mind that TREM2 regulates microglial expression of ApoE, 289 it is tempting to speculate that an interplay between TREM2 and ApoE may underlie faulty lipid efflux and consequent LDs accumulation in the context of AD pathology.

To summarize, defects in lipid metabolism in brain-resident immune cells are highly impactful for AD pathology. Alterations in brain lipid composition and lipid transport and storage are strongly associated with the inflammatory activation of microglia and astrocytes in AD. Remarkably, the convergence of defective lipid metabolism with the pathological activation of glial cells, ultimately culminates in disrupted neuron-glia interactions.

BRAIN-RESIDENT IMMUNE CELLS IN ALZHEIMER’S DISEASE: LET’S TALK ABOUT SEX

AD affects both men and women. However, over the last decades, scientific advances have highlighted the crucial role of sex differences in the heterogeneities of AD prevalence and severity.290 –292 Along with advanced age and APOE4 genotype, female sex appears as a major risk factor for onset of sporadic AD. Indeed, women have a higher risk of developing AD than men, 293 representing two-thirds of all clinically diagnosed AD cases.294,295, 294,295 Importantly, women also exhibit faster cognitive deterioration, and more severe pathology than men.296,297, 296,297 For instance, a cross-sectional study examining a postmortem cohort of nearly 1500 individuals involved in two community-based longitudinal studies of ageing and dementia revealed that women exhibit a faster cognitive decline than men, even in the presence of similarly high Aβ burden. 298 Furthermore, women also exhibit a higher NFTs density. 298 Interestingly, despite being a genetic risk factor for both sexes, women carrying APOE4 allele have a greater risk of developing AD, show accelerated progression of the disease, and have more severe memory and cognitive decline than men.299,300, 299,300 More recently, Wang and colleagues301,302, 301,302 provided further evidence that APOE4 differentially impacts AD pathology in a sex-dependent manner. Women carrying APOE4 allele were found to be more vulnerable for tau pathology and neuroinflammation, particularly in the presence of amyloidosis. Of note, a positive correlation was denoted between Aβ load and microglial activation in women carrying APOE4 allele when compared with men.301,302, 301,302

Due to their natural reproductive history, it has been proposed that women are more susceptible to brain metabolic changes. 303 Progress in preclinical and clinical investigation proves the role of the loss of protective sex hormones at the menopause as drivers of metabolic disturbances in the brain, increasing the risk of women to develop AD. 304 This is not surprising considering that 17β-estradiol, the main estrogen produced not only by peripheral glands (ovaries), but also within the CNS, modulates glycolysis, TCA cycle, OXPHOS efficiency and the oxidative stress status.303,304, 303,304 Using the FDG-PET tracer, a 2-year longitudinal study unveiled a more pronounced glucose hypometabolism in women with AD compared with men. 305 Converging evidence suggests that differences in mitochondrial mechanisms and metabolic switches may be in the root of the increased predisposition and vulnerability of women to develop AD. 306 Employing a cross-species methodology to assess metabolic modifications in the serum and brain of AD individuals and several experimental models of the disease, Demarest and collaborators 306 identified a specific impairment in mitochondrial complex I in female 3xTgAD mice brain cortical synapses, but not in males. Additionally, in non-synaptic, glial-enriched mitochondria from the brain cortex and hippocampus an increase in complex II-dependent respiration was also observed in female AD mice, which indicates a glial upregulation of FFAs metabolism, probably to counterbalance neuronal glucose hypometabolism in AD. 306 Consistently, in female 3xTgAD mice it was found that reproductive senescence paralleled a significant brain mitochondrial bioenergetic decline, as reflected by impaired PDH and cytochrome c oxidase activities and mitochondrial respiration. An early increase in the expression of proteins involved in mitochondrial β-oxidation of long-chain FAs to generate acetyl-CoA, as well as in the conversion of ketone bodies into acetyl-CoA were also detected in the brain of female 3xTgAD mice. 307 Importantly, this early activation of ketolytic and/or FAs oxidation pathways has been proposed as an alternative source of energetic substrates to compensate mitochondrial bioenergetic decline. 308 So, at this point, a major question invades our mind: is immunometabolism a contributing factor underlying AD-related sex differences? Taking advantage of the recent innovations in metabolomics and transcriptomics tools, Hou and collaborators investigated the sex-specific differences in microglial immunometabolism using a network-based multi-omics analytic framework. 309 In detail, these researchers found that female AD individuals exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated IL-10 pathway activity. Additionally, a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocytes was also observed in female AD individuals. 309 Moving to the preclinical findings, Guillot-Sestier and collaborators reported that microglia isolated from female APP/PS1 mice were more glycolytic and less phagocytic, these alterations being accompanied by increased Aβ burden. On the opposite, microglia isolated from male APP/PS1 mice were amoeboid and with a reduced Aβ plaque load, indicating sex-related differences in microglia in terms of morphology, metabolism, and function. 160 Using fluorescence lifetime imaging microscopy in rodents, it was recently observed that the female brain becomes more glycolytic and less oxidative with aging, when compared with the male brain. 310 Interestingly, microglia from aged female brain express more glycolytic genes alongside with typical genes of DAM phenotype (i.e., APOE and TREM2). Similarly, studies performed in human monocyte-derived microglia-like cells revealed higher DAM signature and GLUT5 gene expression in cells derived from middle-aged females compared to males. 310 More recently, an in-depth single-cell transcriptomic analysis identified a female-enriched and disease-associated microglia population, specifically characterized by a high expression level of APOE and TREM2, that is more prevalent in female sporadic AD individuals with an APOE4 background, and thus contributing to sexual dimorphism in AD. 311 Lastly, using counterfactual causal inference models with human neuropathological data, Casaletto and colleagues 312 concluded that microglial activation mediates the relationship between Aβ and tau burden in females but not in males.

Overall, these findings illustrate a crucial role of microglial immunometabolism in biological sex-specific clinical and neuropathological phenotype of AD.

FINAL REMARKS

Far from the classical “neurocentric” perception of AD, in recent decades a more integrated vision of the intricate interplay involving neurons, microglia and astrocytes reveals a complex landscape of potential contributors to the etiology of this devastating neurodegenerative disease. Persistent and self-fueling inflammatory processes represent a major driving force that characterize the progressive nature of AD. The expanding field of immunometabolism has recently attracted the attention of the scientific community to the crosstalk between the metabolic status and immune response. Within this scenario, we have provided a comprehensive and in-depth discussion on the different immunometabolic patterns of microglia and astrocytes during the pathological trajectory of AD (Fig. 1). Particularly, coupled with a reduced phagocytic Aβ clearance, AD microglia exhibit a metabolic switch towards glycolysis, defective mitochondrial function, and LDs accumulation. In turn, AD astrocytes also suffer a metabolic reprogramming characterized by a downregulation of TCA cycle and OXPHOS components and a notorious defect on lipid efflux and massive increase in LDs content. At this point, it is plausible to question if targeting immunometabolism could represent a feasible strategy to counteract AD pathology in a timely manner. Could immunotherapies be more effective than Aβ and tau-directed therapeutics? Novel therapeutics aimed to “abate” neuroinflammation, for instance by targeting TREM2, have entered into clinical trials. 313 However, considering the heterogeneity of astrocytes and microglia phenotypes along the AD continuum, exerting both neuroprotective and neurodegenerative effects, it will be a hard task to define a therapeutic time window to only eliminate the potentially “dangerous” effects of neuroinflammatory events. That said, more basic and translational studies are required to understand the full-bloom AD phenotype and to move a step towards a cure for this neurodegenerative disorder.

Fig. 1

Schematic illustration of microglial and astrocytic metabolic reprogramming in Alzheimer’s disease (AD). The cardinal pathological features of AD are the extracellular deposition of amyloid-β (Aβ) peptide in senile plaques and the presence of intraneuronal tau aggregates forming the neurofibrillary tangles (NFTs), which are typically accompanied by synapse and neuronal loss, as well as neuroinflammation and reactive gliosis. Altogether, these alterations contribute to the brain atrophy and cognitive decline that characterizes this neurodegenerative disease. Fruitful advances in the immunometabolism field identify several metabolic alterations in both microglia and astrocytes during the pathological trajectory of AD. AD microglia exhibit a reduced phagocytic Aβ clearance, a metabolic switch towards glycolysis and an accumulation of lipid droplets (LDs). AD astrocytes present a reduction in glucose uptake, tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), diminished branch-chained amino acids (BCAAs) and free fatty acids (FFAs) metabolism, inefficient lipid transport and LDs accumulation.

AUTHOR CONTRIBUTIONS

Sonia Correia (Conceptualization; Writing – original draft); George Perry (Writing – review & editing); Paula I. Moreira (Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This work was supported by the European Regional Development Fund (ERDF), through the COMPETE 2020–Operational Programme for Competitiveness and Internationalization, and by Portuguese national funds via FCT—Fundação para a Cincia e a Tecnologia under projects UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020. Sónia C. Correia has a Post-Doctoral Researcher Contract DL57/2016 (#SFRH/BPD/109822/2015) from FCT.

CONFLICT OF INTEREST

George Perry and Paula I. Moreira are Editorial Board Members of this journal but were not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

George Perry is a scientific advisor and owns equity in Synaptogenix.

Sónia C. Correia has no conflict of interest to report.

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