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

Abstract

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.

Adult neurogenesis in Alzheimer's disease

“…We currently do not know the full mechanisms(s) by which AHN is impaired in AD, which should be complex and diverse. Mounting evidence from in vivo and in vitro studies showed the presence and levels of Aβ and pTau contribute to AHN impairment in AD (for review, (Culig et al, 2022; Farioli‐Vecchioli et al, 2022; Liu et al, 2021); the references cited in the review papers). Moreno‐Jiménez et al indeed found that the number and maturation of adult‐born neurons declined progressively with the advancement of Braak stages in AD patients (Moreno‐Jiménez et al, 2019).…”

Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound

“…One possible mechanism through which tau can impact on adult hippocampal neurogenesis could be through its accumulation in the hyperphosphorylated form in GABAergic interneurons of the DG in both AD patients and in the 3xTg-AD transgenic mouse model of AD [ 63 ]. Consequently, the reduction of GABA and the disinhibition of local circuits and astrogliosis could in turn impair adult hippocampal neurogenesis [ 64 ].…”

“…Adult hippocampal neurogenesis has several potential functions such as increasing resilience against stress, enhancing pattern separation [ 89 ], the formation of memory and learning [ 90 , 91 ] and inducing the loss of established or old memories [ 92 ]. Indeed, AD mouse model studies have shown that altered neurogenesis was linked to deficits in pattern integration, pattern separation, and cognitive flexibility [ 64 ]. In a study conducted by Nakashiba et al, it was reported that older neurons are mainly implicated in pattern completion as they recognize relatively distinct situations, while younger neurons are essential for the fine discrimination of close contexts.…”

“…Additionally, a timely clearance of old memories will improve the efficiency in developing and storing recent memories within the already existing hippocampal network [ 20 , 95 ]. Since the hippocampus and EC are two key regions involved in memory and they are particularly vulnerable to neurodegeneration and are the first affected during the AD pathogenesis, deficits in neurogenesis probably play a significant role in this disease [ 64 ].…”

Post-Stroke Environmental Enrichment Improves Neurogenesis and Cognitive Function and Reduces the Generation of Aberrant Neurons in the Mouse Hippocampus

“…The process of neurogenesis is influenced by pathologies, such as stroke and other brain lesions, psychiatric diseases or epileptic seizures [19,[22][23][24][25]. In particular, after an experimental stroke, there is an increase in neurogenesis, as reflected by enhanced proliferation and differentiation of stem cells, which depends on the size of the infarcts [26][27][28].…”