Neurogenesis and Alterations of Neural Stem Cells in Mouse Models of Cerebral Amyloidosis

Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer’s disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature on AHN and its impairments in AD.

Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer’s disease (AD) induced by a combination of toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD.

The deposition of amyloid-β (Aβ) peptides in plaques and intracellular neurofibrillary tangles are the two main characteristic pathological features of Alzheimer's disease (AD). Significantly, plaques are surrounded by activated astrocytes, microglia, and possibly, macrophages, and it has been suggested that this activity contributes to the pathology. Whether this will lead to a decrease or an increase in the amount of Aβ deposition is not clear. To investigate the relation between amyloid neuropathology and inflammation, we examined the changes in amyloid pathology in the hippocampus and neocortex following three anti-inflammatory treatments aimed at reducing the amyloid burden. In these studies we treated mice with different non-steroidal anti-inflammatory drugs for several months (i.e., from 8 through 14 months of age), and studied the Aβ pathology and inflammation in the brain. Sham treatment and flurbiprofen treatment did not affect Aβ pathology, and a low dose HCT 1026 (10 mg/kg; a nitric oxide-donating flurbiprofen analog that has additional useful properties, including a remarkable gastrointestinal safety) did not affect pathology either, however a higher dose of HCT 1026 (30 mg/kg) did reduce the Aβ load. Furthermore, this treatment reduced the amount of microglial activation surrounding plaques. In contrast, the low dose of HCT 1026 increased GFAP activation, but did not change microglial activation. Together the data indicate that changing the activity of glial cells can lead to both a decrease of the amyloid burden, and to detrimental changes, likely caused by the interplay between the activation levels of astrocytes and microglial cells.

The generation and cell death of newly generated cells have critical roles in brain development and maintenance in the embryonic and adult brain. Alterations in these processes are also seen in neurodegenerative diseases. Genes that are key players in neurodegenerative diseases (α-synuclein, presenilin-1, tau, huntingtin) are also physiologically involved in modulating brain plasticity. Interestingly, in some neurodegenerative diseases, the specific alterations in neurogenic areas such as the dentate gyrus and subventricular zone/olfactory bulb system parallel the early or premotor symptoms that are seen in the early stages of these diseases, such as depression, anxiety or olfactory dysfunction. We will review the modulation of neurogenesis in animal models and human brains of Parkinson's disease, Huntington's disease and Alzheimer's disease.

Alzheimer's disease (AD) is age‐related progressive neurological dysfunction. Limited clinical benefits for current treatments indicate an urgent need for novel therapeutic strategies. Previous transcriptomic analysis showed that DMP1 expression level was increased in AD model animals whereas it can induce cell‐cycle arrest in several cell lines. However, whether the cell‐cycle arrest of neural progenitor cell induced by DMP1 affects cognitive function in Alzheimer‐like mice still remains unknown. The objective of our study is to explore the issue. We found that DMP1 is correlated with cognitive function based on the clinical genomic analysis of ADNI database. The negative role of DMP1 on neural progenitor cell (NPC) proliferation was revealed by silencing and overexpressing DMP1 in vitro. Furthermore, silencing DMP1 could increase the number of NPCs and improve cognitive function in Alzheimer‐like mice, through decreasing P53 and P21 levels, which suggested that DMP1‐induced cell‐cycle arrest could influence cognitive function.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder associated with progressive cognitive decline and extensive neuropathology throughout the brain. Its main features include limited cell loss in selected subregions, generalized brain atrophy, and gradual accumulation of β-amyloid plaques and neurofibrillary tangles in several brain regions. One of the earliest and most prominently affected brain regions is the hippocampus, a brain structure involved in learning and memory that displays prominent cell loss in its CA1 subregion as well as abundant plaque and tangle pathology.Recent studies have identified the presence of stem cells in brains of adult rodents, primates, and also humans. Only in a few subregions do these stem cells continue to proliferate and differentiate to form new neurons within the mature brain, a process known as adult neurogenesis. Adult neurogenesis occurs in the hippocampal subgranular zone and in the subventricular zone of the lateral ventricles and olfactory bulb. These adult-generated neurons are involved in learning and memory and respond well to various hormonal and environmental factors, like stress, age, physical exercise, and also, surprisingly, to hippocampal insults. With the discovery of functional adult neurogenesis and increasing insights role in cognition and into its environmental control, hopes have risen that stem cells in the adult brain could one day be used to modulate neurodegeneration, and/or cognition e.g., by stimulating neuroregeneration. In this chapter, we discuss properties of stem cells and neurogenesis and their changes during the development of neuropathology and functional deficits in Alzheimer’s disease and some of its main animal models. In addition, we discuss possibilities to stimulate stem cells and neurogenesis for therapeutic purposes in relation to dementia.KeywordsDementiaCognitionAlzheimer’s diseasePresenilinAbAPPHippocampusRegenerationFunctional recovery

The effects of compounds interfering with gamma-secretase, the enzymatic complex responsible of the formation of the amyloid-beta (Abeta) peptide from amyloid-beta protein precursor (AbetaPP), on plaque deposition in transgenic mouse models of Alzheimer's disease are known but scanty data are available on the effects of these drugs on brain plasticity. We evaluated the effects of long-term treatment with CHF5074, a new gamma-secretase modulator, on hippocampal neurogenesis, cortical synaptophysin levels, and contextual memory in transgenic mice carrying the double Swedish mutation of AbetaPP (Tg2576). Six-month old Tg2576 mice were treated with CHF5074 (375 ppm in the diet) up to 15 months of age. Age-matched control transgenic and wild-type mice received standard diet. Compared to wild-type animals, transgenic controls showed a significant decrease in the number of doublecortin-positive neuroblasts in dentate gyrus, synaptophysin intensity in the cortex, freezing to context in the contextual fear conditioning test. Compared to transgenic controls, CHF5074 treatment of Tg2576 mice resulted in a significant attenuation of the neurogenesis impairment in hippocampus (p=0.036), normalization of synaptophysin levels in cortex (p< 0.001), attenuation of plaque burden in the cortex (p=0.033), increases astroglial reaction around plaques (p=0.001), and attenuation of activated microglia (p=0.040). These effects were associated to a complete reversal of contextual memory deficit (p=0.006). Contextual memory significantly correlated with synaptophysin immunoreactivity in the cortex (r=0.548, p=0.0038).

Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer's disease. Adult hippocampal neurogenesis is regulated by intrinsic and extrinsic factors; one of them is diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis studies in Alzheimer's disease and focuses on the role of diet. The review highlights some of the key dietary compounds and interventions such as calorie restriction, fat, polyphenols, zinc, folate, alcohol and thiamine, and emphasizes the pathways that they modify.

Altered proteolytic processing of the β-amyloid precursor protein (APP) is a central event in familial and sporadic Alzheimer's disease (AD). In a process termed regulated intramembrane proteolysis (RIP), APP first undergoes ectodomain shedding executed either by α- secretases at the plasma membrane or by β-secretase in the endosomal compartment. The remaining membrane-anchored stubs are cleaved within the membrane plane by the γ-secretase complex, releasing the APP intracellular domain (AICD) into the cytosol and leading to the generation of the Aβ peptide in the amyloidogenic pathway that is initiated by β-secretase. The Aβ peptides aggregate to form soluble oligomers and finally deposit into amyloid plaques that are a hallmark of AD. Recent evidence indicates a role for Aβ oligomers in regulating synaptic plasticity with excess amounts of oligomers disrupting synaptic function. The amyloid cascade hypothesis of AD is centered on the Aβ peptide, the APP fragment that has been most intensely studied, while other cleavage products have been largely neglected. The secreted ectodomain generated after α-cleavage in the non-amyloidogenic pathway has neurotrophic and neuroproliferative activities, thus opposing the neurotoxicity observed with high concentrations of Aβ. Further, in analogy to many other membrane proteins that are subject to RIP, AICD can translocate to the nucleus to regulate transcription. Many RIP substrates are localized to the synapse and thus could convey a direct signal from the synapse to the nucleus upon cleavage. Evidence indicates that only the amyloidogenic pathway generates AICD capable of nuclear signaling, due to the subcellular compartmentalization of APP processing. In aging and sporadic AD there is an increase in β-secretase levels and activity generating more Aβ peptides and concomitantly leading to an increase in AICD nuclear signaling. In this review, I summarize the current knowledge on AICD nuclear signaling and propose mechanisms to explain how this physiological function of APP might impact the pathology seen in AD.

Abstract Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer’s disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer’s disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8 month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults.