The Multifactorial Etiopathogenesis of Alzheimer’s Disease: Neuroinflammation as the Major Contributor

INTRODUCTION

Alzheimer’s disease (AD) is the most prevalent cause of dementia in people older than 65 [1]. One of the major drawbacks of AD is currently the lack of an effective therapy. During the last several years, much effort has been made to develop a therapy to control the cognitive decline associated with AD. The principal target of this therapy has been amyloid-β (Aβ), which is now, due to the evidence provided, failing due to the lack of results and misinformation [2]. Furthermore, it is now demonstrated that senile plaques have no influence on cognitive decline as no correlation was found [3, 4]. However, soluble Aβ_1 - 42 oligomers can act as an activator of microglia [5, 6], as a danger signal to promote an inflammatory microenvironment, similar to advanced end glycan products (AGEs) [7].

This sheds light on the tau theory. Hyperphosphorylation of tau leads to conformational changes that are directly related to cognitive decline. The cognitive decline, at the same time, is associated with neurodegeneration related to neuroinflammatory processes mediated by danger signals [8–12]. This connection of glial activation with the inflammatory cascade has been known as The Neuromodulation Theory and is the basis for the search of new therapeutic components for AD (see Fig. 1).

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Fig. 1

Representative diagram of the Neuroimmunomodulation Theory. In this unifying theory, damage signals (such as AGEs, fragments of hyperphosphorylated tau, oxidative radical, soluble Aβ peptides, etc.) activate the resting microglia in the brain, which activates several inflammatory signaling cascades that leads to the production of pro-inflammatory cytokines. In a healthy neuron, this triggers a dysregulation of CDK5 kinase which in turn hyperphosphorylates tau and this tau, after the neurodegeneration takes place, acts as a damage signal in other microglia in a positive feedback loop.

THE NEUROIMMUNOMODULATION THEORY: A BRIDGE INTEGRATING THE SEVERAL FACTORS OF AD

The unifying neuroimmunomodulation theory represents the common point between the several etiological origins of AD, hyperphosphorylated tau generating neurofibrillary tangles and soluble Aβ peptide just to mention a few (see Fig. 1). According to this theory, proinflammatory cytokines are released after the activation of the microglia due to damage signals (e.g., soluble Aβ, paired helical filament fragments, oxidative molecules, etc.) which in turn activates signaling cascades that leads to hyperphosphorylation of tau in a cyclic process [13, 14]. Thus, tau neurofibrillary tangles activate the microglia in a positive feedback process (see Fig. 1).

This theory is one of the most important milestones in AD research, providing a novel view in the field, which up until recently was based mostly on Aβ peptide misfolding and senile plaque appearance. Contrarily, it has been demonstrated that senile plaques are also present in the cognitively normal elderly population.

Another connecting point between the neuroimmunomodulation theory and the etiopathology of AD is related to the glucose metabolism impairment observed in AD patients. It has been observed that advanced glycation end products (AGEs) can act as danger signals that activate microglia [15]. Additionally, uncontrolled diabetes leads to a high production of AGEs, which might be one of the etiological origins of AD [16]. Furthermore, AD due to glucose metabolism impairment could now be considered as diabetes type 3 [17].

POTENTIAL BENEFITS OF THE APPLICATION OF THIS THEORY IN THE CLINIC

An additional benefit from this neuroimmunomodulation theory is that it provides a solid basis for the generation of multitarget bioactive compounds beneficial to treat AD, and also early-detection biomarkers.

BRAIN HOMEOSTASIS AND THE BLOOD-BRAIN BARRIER

Immunological changes in AD are not confined to the central nervous system, and AD-associated systemic immune changes appear to affect brain homeostasis. In AD, the permeability of the blood-brain barrier (BBB) is increased due to the decreased expression of the tight junction molecules in vascular endothelial cells [28]. Moreover, an increase of adhesion molecules (ICAM-1, VCAM-1) is observed in the AD BBB endothelium, potentially contributing to immune cell migration [29]. Emerging evidence supports that T and B cell infiltration into the brain exacerbates neuroinflammation and accelerates neuronal death. Although the significance of T cells in AD pathogenesis is still debated, elevated peripheral Th1 and Th17 cells have been associated with the release of proinflammatory molecules [28]. Higher levels of cytokines (IL-6 and IL-1b), and chemokines (CCL5, CXCL9) have been detected in the AD periphery and brain [29]. CD8+ and CD4+ T cells also have been found in the brain parenchyma of AD patients which could contribute to AD progression by acting on neurons and functional properties of microglia through the release of proinflammatory factors [30]. Besides, B cell infiltration seems to contribute to immunoglobulin deposits [31], acting also as a modulator of neuroinflammation; hence the importance of research into key players of neuroimmunomodulation to develop therapeutic interventions in AD.

DISCUSSION

In this article, our aim was to shed light to some of the etiological origins of AD and how the neuroimmunomodulation theory is a bridge integrating them (see Fig. 2).

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Fig. 2

Alzheimer’s disease as multifactorial disease. One single factor is not sufficient to trigger Alzheimer’s disease. All the etiopathological hallmarks converge in the neuroinflammatory process, direct or indirectly, and continue to exacerbate the pathology due to the cyclic events taking place.

AD has long gone from the molecular hallmarks, in particular with the Aβ hypothesis. However, tau is also a molecular hallmark, and it has a better correlation with cognitive decline and clinical observations.

AD is a multifactorial disease and should be considered as such. The latter is one of the main reasons why current therapeutic approaches have been unsuccessful, as the majority have been directed against Aβ. The neuroimmunomodulation theory includes the majority (if not all) of the etiological origins of AD that lead to a common path: neuroinflammation triggered by activation of microglia and also astrocytes. The latter, consequently, leads to neurodegeneration that becomes the onset of AD.

Thus, all these multifactorial components converge at some point in which a neuroinflammatory microenvironment is triggered. Thus, all the molecular hallmarks, such as soluble Aβ, tau, or AGEs should be considered as danger signals, independently of their correlation with the cognitive decline. However, the correlation with cognitive decline is key to choose a proper target in the search of an early detection biomarker and effective potential therapies. And until now, tau is the one best candidates in that regard. Could there be other targets? No doubt, but by aiming at multiple targets, the best results can be obtained to develop an effective therapy. The multitarget therapy is currently one of the best options in AD.

CONCLUSION

AD is a multifactorial disease with a complex etiopathogenesis. The amyloid theory alone is not sufficient to explain the physiopathology. In that regard, the neuroimmunomodulation theory converges several etiological origins of AD, such as amyloid and tau aggregation, glucose metabolism impairment, etc., by stating that the main onset of AD is the neuroinflammatory process that takes place after the chronic activation of the microglia. All the etiological components are now part of this theory as damage signals that activate the microglia, which is the starting point for the neuroinflammatory processes that eventually lead to neurodegeneration. Those danger signals might be a useful tool as an early detection biomarker, but the correlation with cognitive decline should be considered first.

In that regard, potential therapies should now focus on this novel approach as the multitarget therapy, currently one of the best options for AD patients.