Science︱ proved in the human body for the first time: a variety of neurodegenerative diseases can affect the neurogenesis of the hippocampal dentate gyrus

Authors︱Editor in charge by Wang Zerui︱Wang Sizhen Adult neurogenesis mainly occurs in specific areas of the adult mammalian brain, such as the hippocampal dentate gyrus and the subventricular zone/olfactory bulb system
.

The process by which neural stem cells produce new neurons in the hippocampus is called adult hippocampal neurogenesis (AHN), and this process can increase the plasticity of the hippocampus
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AHN is very important in learning, memory and emotional regulation, and is related to memory deficits [1, 2]
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It has been confirmed in previous studies of mouse models that the new neurons are mainly derived from neural stem cells in the subgranular region of the hippocampal dentate gyrus [1]
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 So why are changes in neurogenesis important to neurodegenerative diseases? Neurodegenerative diseases are related to pathological protein misfolding, which is accompanied by the loss of neurons in different brain regions, and at the same time the endogenous ability of adult brain cells to renew and the function of new neurons are also impaired
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Therefore, changes in neurogenesis are a common feature of neurodegenerative diseases
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The cognitive impairment and related psychiatric symptoms caused by neurodegenerative diseases have a strong correlation with the damage of hippocampal function and structure, and its underlying neurodegenerative process can also change the plasticity of the hippocampus and increase its vulnerability
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Therefore, in the context of different neurodegenerative diseases, different sensory, emotional and cognitive impairments may be related to changes in neurogenesis
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However, as of now, the link between AHN and hippocampal function, and the link between AHN and neurodegenerative diseases have not been confirmed in humans
.

 On October 21, 2021, the M.
Llorens-Martín research group from the Severo Ochoa Molecular Biology Center of the Autonomous University of Madrid, Spain published an article entitled "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis" on Science (First release) , By studying the homeostasis of the hippocampal dentate gyrus micro-niche and the dynamics of AHN in human autopsy specimens, the potential connection between AHN and hippocampal function was confirmed for the first time, and the influence of AHN on different neurodegenerative diseases was confirmed, including Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Lewy body dementia (LBD), and frontotemporal dementia (FTD)
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 First, the authors tested AHN in neurological healthy control subjects (Figure 1)
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It is known that the human dentate gyrus contains immature dentate granule cells (DGCs), but is it similar to the mouse model that there are radial glia-like cells (RGL) with neural stem cell functions? ) Cells), has not been confirmed [3,4]
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Here, through the detection of human autopsy specimens, the authors discovered Nestin+ cells with neural stem cell characteristics and expressed RGL-related markers, such as Sox2 (SRY-box 2), Vimentin (vimentin), GFAP (Glia Fibrillary Acidic Protein)
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These Nestin+ cells have a certain morphological similarity with hippocampal neural stem cells.
For example, the cell bodies of Nestin+ cells are distributed in the subgranular area of ​​the equine dentate gyrus
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At the same time, some proliferative cells can also be detected in the subgranular area, including phosphohistone 3 (PH3) + proliferative cells, HuC/HuD + proliferative neuroblasts
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The existence of these Nestin+ cells suggests that the human hippocampal neural stem cell pool exists throughout life
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Consistent with the previously reported results, these human DGCs have been identified as precursor granule cells with neurogenic capabilities [5], maintaining the proliferation ability of neural stem cells [6]
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 Immature DGC undergoes different differentiation stages before maturation, and a variety of neuronal markers are known to characterize the maturation and differentiation stages of DGC, such as the microtubule-associated protein doublecortin (DCX) to characterize immature neurons, HuC/ HuD characterizes proliferative neuroblasts, and NeuN (neuronal nucleus), 2MAP-2 (microtubule-associated protein 2), 3R Tau, calcium binding protein (CB), etc.
characterize more differentiated DGCs
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The expression of these markers changes during the process of DGC maturation, and the cell location and neurite direction will change
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As shown in Figure 1, the most immature DGCs, DCX and CR are located in the subgranular layer (SGZ), with small and horizontally oriented primary apical neurites; more differentiated DGCs appear, and DCX and CB occupy the granular cell layer ( The upper position of GCL) is larger and has a single primary apical neurite; next, the detection of NeuN and DCX in DGC indicates the intermediate state of DGC maturity
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Therefore, this dynamic change of DGC indicates the dynamic characteristics of human AHN
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Figure 1 Different stages of AHN in neurologically healthy control subjects (Source: J.
Terreros-Roncal et al.
, Science, 2021) Rodent model studies have shown that AHN is affected by neurogenic micro-niches in the symptomatic gyrus.
niche), including astrocytes, microglia and vascular system [8, 9]
.

In this study, the author also observed that in addition to a large number of immature DGC and RGL cells, there are also abundant astrocytes and microglia on the surface of the granular cell layer (GCL) of the healthy human dentate gyrus.
Cell
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Among them, microglia regulate AHN by controlling the maturation of newborn neurons [7]
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Interestingly, the author noticed that microglia exhibited a special membrane structure: "phagocytic pouches" (Figure 2), cells with phagocytic dysfunction, which are phagocytic pouches in healthy elderly subjects.
The decrease in the number of pockets indicates that the phenotype of microglia has a local functional disorder; the change of microglia function may be one of the basic mechanisms of age-related AHN reduction in humans
.

Figure 3 Microglial cells engulf the pouch (Source: J.
Terreros-Roncal et al.
, Science, 2021) Next, the author examines the changes in AHN in different neurodegenerative diseases (Figure 3)
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First, the susceptibility of AHN to amyotrophic lateral sclerosis (ALS) was tested
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It was found that the density of PH3+proliferative cells and HuC/HuD+proliferative neural stem cells in the dentate gyrus of ALS patients remained unchanged, indicating that the hippocampus retains the ability to proliferate in ALS
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The density of neural stem cells and immature DCX+DGC increases, and the morphological development of DGC is impaired
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The author also examined the neurogenic microecology in the dentate gyrus and found that astrocytes proliferate, the number of microglia phagocytic pockets is reduced, and capillaries are thickened
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These results indicate that both AHN and the homeostasis of the neurogenic niche in the dentate gyrus are susceptible to ALS
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The author then studied the effects of Huntington's disease (HD) on AHN
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It was found that the density of Sox2+ cells and proliferative cells did not change, but the density of Nestin+ neural stem cells and immature DGC increased
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Immature DGC showed premature damage, abnormal morphology, and decreased NeuN expression
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The homeostasis of the neurogenic microniche in the dentate gyrus is also affected similarly to the above-mentioned ALS
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These results indicate that the susceptibility of AHN and dentate homeostasis to HD is increased.
In newborns with HD, DGC exhibits early and late mature damage, leading to its stay in the undifferentiated stage
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Next, the authors examined the effect of α-synucleinopathy on AHN
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Parkinson's disease (PD) and Lewy body dementia (LBD) are the two most common α-synuclein diseases
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This study found that patients with these two diseases showed increased RGL cell density and abnormal morphology of immature DCX+ DGCs
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PD patients and non-LBD patients showed increased density of HuC/HuD+proliferative neuroblasts and DCX+immature DGC, and decreased NeuN expression
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In the detection of neurogenic micro-niches, both PD and LBD patients showed increased dentate gyrus capillary thickness, and PD patients also found impaired phagocytic ability of microglia and dentate gyrus astrocytes Hyperplasia
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These results indicate that these two α-synucleinopathy target the dentate gyrus environment and produce similar AHN characteristics, but PD patients show more severe damage, and LBD patients have changes in AHN and dentate gyrus neurogenicity.
The impact of micro-niche changes is relatively mild
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Finally, the authors found that patients with frontotemporal dementia (FTD) also showed slight changes in AHN
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The main manifestations are that the density of neural stem cells and immature DGCs remains unchanged, but the density of HuC/HuD+ proliferative neurons is reduced, and DGC differentiation is slightly impaired
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The neurogenic micro-niche of the dentate gyrus is also slightly affected, manifested as astrocyte proliferation, capillary thickness increase, and the phagocytic capacity of microglia show an exponential decrease
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These results indicate that FTD can affect AHN by changing the balance of the ratio of RGL cells and proliferative cells, causing abnormal morphological dentate granular cells, and disturbing the neurogenic micro-niche of the dentate gyrus
.

Figure 3 Changes in AHN in various neurodegenerative diseases (Source: J.
Terreros-Roncal et al.
, Science, 2021) Conclusion and discussion, inspiration and prospects of the article It explores the changes of AHN in different periods under normal physiological conditions and related influencing factors, and studies how the neurogenic micro-niche of the dentate gyrus of healthy people is regulated and how it affects AHN
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 It also revealed the susceptibility of human AHN to different neurodegenerative diseases for the first time
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In different neurodegenerative diseases, AHN changes to different degrees, the ratio of GCL cells and proliferating cells (such as proliferative neural stem cells) to different degrees, and the homeostasis of neurogenic micro-niches
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In short, these changes are different for different diseases and the severity of the same disease
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 The study also found that both normal aging and neurodegenerative diseases reduce the phagocytic capacity of microglia, trigger astrocyte proliferation, and change the vascular system of the dentate gyrus, and there have been reports that these changes will affect AHN [8, 9], thus suggesting that AHN damage may be a common mechanism of hippocampal dysfunction in human normal physiological aging and disease pathological aging
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Therefore, in future studies, revealing the relationship between the neurogenic micro-niche factors of the human dentate gyrus and the dynamic factors of AHN will help us understand the physiological functions of AHN, especially the effect of AHN on the brain during the entire human life.
The physiological function of plasticity
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 It is also worth noting that, for example, the number of autopsy specimens in this study is not large enough (48 cases in total), so whether it has a certain universality remains to be further verified
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In addition, Alzheimer's disease, a relatively common neuropromoting disease, has not been tested in this article, and the reason has not been clarified
.

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