Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery

The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer’s disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.

MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer’s Disease

Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.

Diabetes and Depression: A Bidirectional Phenomenon

Diabetes mellitus is a strong molecular etiological upstream event that leads to different pathological problems like Cardio-vascular disease, nephropathy, neuropathy, retinopathy, hearing loss, and immunological disturbances, the most common of which is depression. Diabetes and depression relationship is thought to be bidirectional, meaning that depression can lead to diabetes and diabetes can assist the onset of depression. Depression is one of the most overlooked symptoms in diabetes patients, and it is strongly related to a decline in quality of life. Several pathological links are discussed in this review, including dysregulation of the hypothalamic pituitary-adrenal (HPA) axis and neurotransmitter systems, particularly the monoaminergic system, the role of oxidative stress, neuroinflammation, and cell death, impaired neurogenesis and BDNF synthesis, particularly in the hippocampus and prefrontal cortex, brain areas that regulate emotional behaviour, and finally, epigenetic factors.

Genes Associated with Disturbed Cerebral Neurogenesis in the Embryonic Brain of Mouse Models of Down Syndrome

Down syndrome (DS), also known as trisomy 21, is the most frequent genetic cause of intellectual disability. Although the mechanism remains unknown, delayed brain development is assumed to be involved in DS intellectual disability. Analyses with human with DS and mouse models have shown that defects in embryonic cortical neurogenesis may lead to delayed brain development. Cre-loxP-mediated chromosomal engineering has allowed the generation of a variety of mouse models carrying various partial Mmu16 segments. These mouse models are useful for determining genotype–phenotype correlations and identifying dosage-sensitive genes involved in the impaired neurogenesis. In this review, we summarize several candidate genes and pathways that have been linked to defective cortical neurogenesis in DS.

Memantine Protects against Paclitaxel-Induced Cognitive Impairment through Modulation of Neurogenesis and Inflammation in Mice

Chemotherapy-induced cognitive impairment (CICI) is an adverse side effect of cancer treatment with increasing awareness. Hippocampal damage and related neurocognitive impairment may mediate the development of CICI, in which altered neurogenesis may play a role. In addition, increased inflammation may be related to chemotherapy-induced hippocampal damage. Memantine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that may enhance neurogenesis and modulate inflammation, may be useful for treating CICI. To test this hypothesis, paclitaxel was administered to eight-week-old male B6 mice to demonstrate the relationship between CICI and impaired neurogenesis, and then, we evaluated the impact of different memantine regimens on neurogenesis and inflammation in this CICI model. The results demonstrated that both the pretreatment and cotreatment regimens with memantine successfully reversed impaired neurogenesis and spatial memory impairment in behavior tests. The pretreatment regimen unsuccessfully inhibited the expression of peripheral and central TNF- and IL-1 and did not improve the mood alterations following paclitaxel treatment. However, the cotreatment regimen led to a better modulatory effect on inflammation and restoration of mood disturbance. In conclusion, this study illustrated that impaired neurogenesis is one of the mechanisms of paclitaxel-induced CICI. Memantine may serve as a potential treatment for paclitaxel-induced CICI, but different treatment strategies may lead to variations in the treatment efficacy.

Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.