Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by restoring the memory-storing neurons

Abstract

Hippocampal neurogenesis is impaired in Alzheimer’s disease (AD) patients and familial Alzheimer’s disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.

Faecal microbiota transplantation from Alzheimer’s participants induces impairments in neurogenesis and cognitive behaviours in rats

“…We also found that AD-FMT rats displayed an impairment in the morphological development of these newborn neurons, rendering a delay or a defect in this critical process of enabling functional integration into hippocampal circuits (Zhao et al 2008, Deng et al, 2010. In line with these findings, intra-species FMT (5xFAD to WT mice) reduced the survival and proliferation of neurons (Kim et al, 2021), and the recruitment and dendritic complexity of immature neurons was deficient in a familial AD mouse model (Mishra et al, 2022). Interestingly, recent studies have shown that that transfer of a WT mouse microbiome into APPswe/PSEN1dE9 mice improved spatial memory and synaptic plasticity (Sun et al, 2019), that reconstitution with normal gut flora in newborn mice protected against decreased AHN and cognitive deficits in antibiotic-treated mice (Liu et al, 2022), and that augmentation of AHN restored the dendritic development of new neurons, coupled with an enhancement of spatial recognition memory (Mishra et al, 2022).…”

“…In line with these findings, intra-species FMT (5xFAD to WT mice) reduced the survival and proliferation of neurons (Kim et al, 2021), and the recruitment and dendritic complexity of immature neurons was deficient in a familial AD mouse model (Mishra et al, 2022). Interestingly, recent studies have shown that that transfer of a WT mouse microbiome into APPswe/PSEN1dE9 mice improved spatial memory and synaptic plasticity (Sun et al, 2019), that reconstitution with normal gut flora in newborn mice protected against decreased AHN and cognitive deficits in antibiotic-treated mice (Liu et al, 2022), and that augmentation of AHN restored the dendritic development of new neurons, coupled with an enhancement of spatial recognition memory (Mishra et al, 2022). Thus, future studies should address whether the changes we observed in adult rats that received FMT from AD human donors are reversible, as well as mechanistic pathways that connect the gut microbiome to AHN.…”

“…Interestingly, the memory impairments observed in rats after FMT from AD donors are reliant on AHN and are supported by a recent study suggesting that defective neurogenesis contributes to memory failure in AD (Mishra et al, 2022). Accumulating evidence suggests that the gut microbiome can impact AHN; germ-free mice display increased AHN (Ogbonnaya et al, 2015), and antibiotic treatment reduced AHN, which was reversed by probiotic treatment in mice, possibly through brain monocytes (Möhle et al, 2016) and voluntary exercise in rats (unpublished observation).…”

Adult-born neurons add flexibility to hippocampal memories

“…Whether these cells are actively generated during adulthood or retained in an immature state is unclear. Further research is required to establish if human neurogenesis has any cognitive benefits or functional implications in neuropsychiatric conditions ( Mishra et al, 2022 ).…”

BI-D1870 Causes the Rats’ Learning and Memory Acquisition Ability Impairment

“…Learning and memory is the most basic neurological function of the human brain, and abnormal nerve tissue structure is accompanied by learning and memory dysfunction [1]. Many neurodegenerative diseases, such as Alzheimer's Disease (AD) exist neuron loss and neural structure damage [2].…”