Impact of Neuroinflammation on Hippocampal Neurogenesis: Relevance to Aging and Alzheimer’s Disease

HIPPOCAMPAL NEUROGENESIS

Adult neurogenesis has been extensively investigated in two main areas of the mammalian brain: the subventricular zone and the subgranular zone of the hippocampal dentate gyrus [1, 2]. Both neurogenic niches maintain a pool of immature cells with stem-cell like properties and give rise to differentiated adult neuronal cells that functionally integrate the brain parenchyma and participate in physiological functions of their target regions; the olfactory bulb and the dentate granular cell layer, respectively, for subventricular and hippocampal subgranular neurogenesis.

The hippocampal neurogenesis is an active process in the adult mammalian brain, including the human brain. Several multistep models have been proposed to schematize the neurogenic cascade. Four distinct phases have been described in the neurogenesis process: 1) precursor cell phase; 2) early survival phase; 3) postmitotic maturation phase, and 4) late survival phase [1, 3].

Late survival phase

This phase is characterized by the consolidation of the glutamatergic transmission and maturation of the electric properties of adult neurons. This process results in significant neuronal death of the pool of young neurons not able to functionally integrate in the mature circuits. In the late survival phase, the postmitotic and differentiated neurons loss the expression of calretinin and up-regulate the calcium binding protein calbindin [3]. In addition, newly generated neurons show enhanced plasticity during this period, showing facilitated/enhanced long-term potentiation [8] (Fig. 1).

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Fig.1

Schematic representation of dentate hippocampal neurogenesis. The subgranular zone hosts a pool of immature cells with radial glia-like morphology and stem cell markers. These cells have low proliferative capacity and generate transient-amplifying cells with short cell cycles, expanding the neurogenic potential of the neurogenic niche (phase 1, precursor cell phase). Young neuroblasts exit the cell cycle into a postmitotic stage, migrate into the granular cell layer, acquire markers of the neuronal lineage, and enter in a critical cell death/survival period (phase 2, early survival phase). Young neurons differentiate a complex dendritic network, project a mossy fiber axon in the stratum lucidum of the hippocampal CA3 area and maturate the synaptic transmission via glutamatergic excitatory synapses (phase 3, phase 4, postmitotic maturation phase, late survival phase).

The fine-tune balance between stemness, differentiation, and survival in the hippocampal neurogenic niche is critical to maintain and sustain neurogenesis across the life cycle and feed differentiated granular cells into the memory circuits of the hippocampus.

The neurogenic niche comprises and is modulated by a diversity of intrinsic, extrinsic, and behavioral factors [9]. Among intrinsic factors, transcription factors and epigenetic modulators are determinant in restraining cells in the immature state or, on the contrary, foster differentiation. A plethora of intrinsic factors have been shown to be of major relevance for the modulation of the hippocampal neurogenic niche [10]. Extrinsic factors comprise extracellular signaling mechanisms triggered by soluble chemical compounds that affect the neurogenesis or signaling molecules involved in cell-cell or cell-extracellular matrix contacts in the neurogenic niche [11, 12].

On the other hand, the neurogenic niche also responds to changes triggered by environmental factors like voluntary physical exercise, environmental enrichment, diet, as well as stress, and depression [13, 14]. The mechanisms that link behavioral changes and the dynamics of the neurogenic niche are not fully understood but involve epigenetic regulation of intrinsic factors expression and signaling mechanisms via extrinsic factors [15].

The control of the dynamics of the hippocampal neurogenic niche seems to be strongly affected by life course habits, raising challenging perspectives for educational strategies of the human populations in order to stimulate physiological neurogenesis in the hippocampus, preserving the cognitive reserve and enforcing the memory resources to support healthy memory in aging individuals.

NEUROGENESIS AND COGNITIVE PERFORMANCE

The continuous addition of new neurons to the dentate granular cell layer plays a key role in spatial memory coding and performance [16–19] and is a key structural component of the cognitive reserve in the hippocampus [20, 21]. Increasing evidence obtained from experiments performed in rodent animals indicates that environmental exposure to cognitive stimulation conditions or to voluntary physical exercise highlights the potential role of the modulation of life-long neurogenesis as a possible booster of the cognitive reserve [22, 23]. Accordingly, if the scientific evidence gathered so far can be translated to the human behavior, new educational strategies may provide future generations more protection to counteract inadequate cognitive aging and better resist to cognitive decline under conditions occurring in Alzheimer’s disease (AD) [24].

THE CROSS-TALK BETWEEN MICROGLIA AND THE STEM CELL NICHE

Microglia are the main resident immune-surveillants of the adult brain. Under physiological non-reactive conditions, microglial cells show a ramified phenotype, constantly sensing the brain parenchyma to monitor the physiological status of the environment, playing a key role in the front line of detection and early reaction to brain aggression or neurodegeneration hallmarks [25].

Many soluble factors are involved in the control of microglia functional status. These factors include ATP released by damaged cells, proinflammatory cytokines, chemokines, adhesion molecules, and microbial signals like bacterial lipopolysaccharides (LPS), hypomethylated DNA, flagellin, double stranded RNA, and other molecules [25, 26].

The neurogenic niche is particularly enriched in challenging cascades related to cell differentiation and cell degeneration, axonogenesis and dendrite pruning, synaptogenesis, synaptic integration, and synaptic plasticity. This plastic environment signals onto surrounding surveillant microglial cells that exert a major modulatory role on progenitor cells fate [27]. It is estimated that between 30 and 40% of neural progenitor cells and neuroblasts contact microglial cells in the hippocampal dentate gyrus. Apoptotic cells removed by microglia mainly correspond to young cells in the intermediate state between late amplifying neuroprogenitor cells and early neuroblasts, or to young postmitotic newborn neurons [28]. Phagocytic cells, including microglial cells, play a key role in the homeostasis of the hippocampal neurogenic niche, ensuring proper survival, differentiation and integration of newborn neurons, but, at the same time, ensure proper removal of cellular components or degenerating cells that could mount an inadequate inflammatory signaling cascade [28–31].

MICROGLIA AND NEUROINFLAMMATION

Microglial cells are the main orchestrators of the neuroinflammatory response in the brain, although other cell types exert an important function, mainly astrocytes. Subsequently to the disruption of the fine-tune equilibrium of the brain parenchyma and cell degeneration or cell stress, microglial cells mount an immediate innate immune response to handle and restrain brain lesion [25].

Although microglial reaction can be quite different under distinct conditions, from the classical point of view, following detection of an abnormal physiological status microglial cells retract their fine process and acquire a reactive-like morphology, allowing rapid migration to brain lesion areas and phagocytosis of potential invader pathogens or degenerated cells. Reactive microglial cells act in synergy with astrocytes to mount an inflammatory reaction, releasing a plethora of pro-inflammatory cytokines and chemokines to further increase the chemoattraction of microglia and macrophages, increase the permeability of the blood-brain barrier, develop a toxic reaction against invader pathogens, and restrict brain injury by mounting a gliotic reaction, mainly due to reactive astrocytes [32].

NEUROINFLAMMATION IMPACT ON MICROGLIAL REGULATION OF ADULT NEUROGENESIS

As previously mentioned, there is a large body of evidence pointing to the involvement of microglia in the neurogenic cascade and cognitive function. In addition, microglial cells may be involved in the crosstalk between life habits and adult neurogenesis/cognitive reserve [27]. Considering the changes that inflammatory processes induce in microglia, we suggest that neuroinflammation should have a detrimental impact on microglial regulation of adult neurogenesis.

While mounting the neuroinflammatory response, microglial cells release several cytokines that are known to influence adult neurogenesis, such as TNF-α and IL-1β, among others [29, 33]. Moreover, acting in close cooperation with microglia, astrocytes may also release these cytokines during inflammation. Importantly, in vitro studies showed that the reduction in the survival of neuroprecursor cells after an inflammatory challenge is mediated by soluble factors released by microglia [31, 34–36]. Cellular elements of the neurogenic cascade express specific receptors for these inflammatory molecules, such as IL-1β receptor (IL1R) and TNF-α receptors 1 and 2 (TNFR1 and TNFR2) [37]. Indeed, cell proliferation in the dentate gyrus is increased when IL-1β or TNF-α receptors are diminished or inhibited [38, 39]. Also, to note that microglial activation may impair neurogenesis indirectly, via the brain endothelium. Endothelial cells modulate the self-renewal and neurogenesis in vascular niches located at the subventricular zone, by releasing several diffusible signals that affect neural precursors, promoting stem-cell renewal and ultimately controlling their fate [12, 41]. However, it has been previously shown that the activation of microglia leads to the release of proinflammatory factors, such as matrix metalloproteinase (MMP)-9, which subsequently weaken the brain endothelium and impairs its physiological functioning [42]. Indeed, studies on the long-term activation of microglia in the subventricular zone depict its importance in the regulation of neurogenesis [43].

The survival of hippocampal neuroprecursor cells is compromised by inflammation, as intraperitoneal administration of bacterial LPS induces the death of these progenitor cells [28]. Differentiation of new neurons is also affected by neuroinflammatory processes. Recently, loss of coxsackievirus and adenovirus receptor, whose expression is reduced under neuroinflammatory conditions, has been related to a decrease in neuroblast maturation [44]. There are also other evidences indicating that both excitatory and inhibitory synaptic integration of newly-generated neurons is specifically affected by LPS-(directly administered into the hippocampus) induced neuroinflammation [45, 46]. Therefore, proliferation, survival, differentiation, and integration of neuroprogenitor cells and new neurons is influenced by neuroinflammatory processes. In general, pro-inflammatory molecules exert a detrimental effect in the net production of newly-generated neurons, although most direct evidences come from cell culture experiments [29, 47].

Age-related changes in microglial activation status, from protective to detrimental, occur with a concomitant decrease in neurogenesis and have been correlated with a decrease in memory performance. With aging, microglial cells overproduce proinflammatory cytokines (including TNF-α, IL-1β, IL-6) and anti-inflammatory cytokines (IL-10, TGF-β1) that affect neurogenesis. Moreover, the “on/off” system made by fractalkine/CX3CR1 also changes creating a major impact in microglia resting state toward activated status and affecting neurogenesis [48]. Decreased levels of CX3CR1 during aging or in knock out animals diminish the production of new hippocampal neurons [48–50], synaptic plasticity, and memory function [49]. Importantly, the effects mediated by decreased expression of CX3CR1 have been related to increased levels of the anti-neurogenic cytokine IL-1β [48, 49]. Interaction of neuronal fractalkine with its receptor maintains low levels of microglial expression of IL-1β. Therefore, neuronal fractalkine signaling to microglial cells indirectly modulates adult neurogenesis and thus, memory function.

Neuroinflammatory processes are well known to affect cognitive capacities, especially early after systemic inflammation, as part of the well know sickness behavior. However, a direct relationship between inflammatory-induced decrease in adult neurogenesis and changes in hippocampal dependent behavior has not been demonstrated [51]. Importantly, the behavioral dependent activation of newly generated neurons is affected by chronic neuroinflammation [52]. In addition, recent evidence highlights the detrimental effect of neuroinflammation in cognitive deficit associated with high-fat diet and type-2 diabetes in AβPPswe/PSEN1dE9 AD mouse model, a process protected by the cholinergic inhibitor rivastigmine through its effect potentiating adult neurogenesis [53]. In our laboratory, we found a close correlation between acute systemic inflammation, inhibition of hippocampal neurogenesis, and spatial memory performance using Morris water maze [54]. The reported differences were remarkable when comparing wild type and triple transgenic mouse model of AD (3xTg AD mice). However, surprisingly, we also found that the induction of an acute and systemic inflammation by intraperitoneal injection with LPS mounts a sustainable long-term neuroinflammatory cascade that (after 6 weeks) decreases the number and synaptic integration of new born neurons in the hippocampus and discreetly compromises memory function [54]. Other studies have also shown that there may be indirect links between the activation of microglia and neuronal impairment, given that morphological changes in premature microglia precede the loss of immature reactive astrocytes and a subsequent delay in myelination [55]. This may be due to a dysfunction in microglia-mediated synaptic pruning, which has been shown to contribute to long-lasting defects in oligodendrocyte maturation and myelination [56] and to neurodevelopmental disorders [57].

Our, and others’, data indicate that there is an important relationship between neuroinflammation, hippocampal neurogenesis, and memory performance (Fig. 2). However, there is no clear understanding about whether there is a direct relationship between the three elements of this triad and how it is articulated. However, we envisage that the development of new tools to manipulate adult neurogenesis and neuroinflammation, and to analyze their effects on behavior will allow unrevealing the secrets of the neuro inflammatory-neurogenic crosstalk and its involvement on brain function.

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Fig.2

Detrimental long-term effect of LPS-induced inflammation in hippocampal neurogenesis, synaptogenesis, and memory function. 3xTg AD mice show a striking inhibition of neurogenesis and cognitive performance when compared with wild type mice. A single and acute systemic inflammatory event mounts a long-term neuroinflammatory cascade that further inhibits neurogenesis and decrease cognitive performance in 3xTg AD mice. Interestingly, in wild type mice, a systemic inflammatory event also impacts on neurogenesis by reducing the integration of newborn neurons, neuroblast complexity, synaptic differentiation, and spatial memory performance (Valero et al. [54]; reproduced with permission from Frontiers in Neuroscience).

CONCLUSION

Neuroinflammation is a double-faced process that is aimed to protect central nervous system integrity, but when prolonged, may induce undesired detrimental side effects. Importantly, neuroinflammation-related detrimental effects have been associated with the development and progression of neurodegenerative conditions, including the onset of the cascade of events that leads to AD [58]. Therefore, it is crucial to determine how neuroinflammatory processes may be resolved to potentiate their protecting effects while avoiding negative repercussions in brain plasticity or the cognitive reserve. Hippocampal adult neurogenesis may be considered as one of the main brain cognitive reserve feeder mechanisms, together with synaptic plasticity. Considering the possible relevance of adult neurogenesis in cognition it is of vital importance to unravel the mechanisms that interconnect both processes neuroinflammation and adult neurogenesis and to know how they are modulated by lifestyle-related factors. Thus, in the near future we will be able to prevent and/or compensate detrimental effects of neuroinflammation by using pro-neurogenic strategies such as cognitive stimulation, physical exercise, or healthy dietary habits.