Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer’s disease

Abstract

In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement.

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan

“…Alternatively, the FMD may increase survival of newly-differentiated neurons, as observed in the dentate gyrus of alternate day-fed rodents (Lee et al, 2002; Mattson et al, 2001). The observed improvements in cognitive performance in the FMD cohort might be affected by an the increase in neurogenesis mediated by PKA/CREB-dependent regulation of NeuroD1 (Cho et al, 2012; Sharma et al, 1999), which is known to increase neuronal survival and differentiation of hippocampal progenitors (Roybon et al, 2009), enhance functional integration of new neurons, and alleviate memory deficits in a mouse model of Alzheimer’s disease (Richetin et al, 2015). …”

Fluoxetine attenuates the impairment of spatial learning ability and prevents neuron loss in middle-aged APPswe/PSEN1dE9 double transgenic Alzheimer's disease mice

“…Furthermore, Demars et al [91] have reported that APPswe/PS1ΔE9 mice exhibit severe impairments in hippocampal neurogenesis at as early as two months of age. These decreases in neurogenesis within the DG have been associated with cognitive impairments linked with AD [92–95]. In addition, Boekhoorn et al [96] have reported that proliferation does occur in presenile Alzheimer hippocampus (patients ranging from 63 to 70 years of age), and this proliferation reflects glial and vascular-associated changes in the CA1-3 areas but not neurogenesis in the DG.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…In APPxPS1 mouse AD models, there are only limited numbers of new neurons generated and the capacity of the new granule cells is reduced in a sex‐unbalanced manner (Richetin, Petsophonsakul, Roybon, Guiard, & Rampon, 2017). NSC transplantation slowed the disease progression in an AD mouse model (Blurton‐Jones et al, 2009), while directed expression of a transcription factor, Neurod1, in cycling hippocampal progenitors could produce population of highly connected new neurons and restore spatial memory in AD mouse model (Richetin et al, 2015). …”