Alzheimer's-Type Amyloidosis in Transgenic Mice Impairs Survival of Newborn Neurons Derived from Adult Hippocampal Neurogenesis

Abstract

Alzheimer's disease (AD) is characterized by severe neuronal loss in several brain regions important for learning and memory. Of the structures affected by AD, the hippocampus is unique in continuing to produce new neurons throughout life. Mounting evidence indicates that hippocampal neurogenesis contributes to the processing and storage of new information and that deficits in the production of new neurons may impair learning and memory. Here, we examine whether the overproduction of amyloid-␤ (A␤) peptide in a mouse model for AD might be detrimental to newborn neurons in the hippocampus. We used transgenic mice overexpressing familial AD variants of amyloid precursor protein (APP) and/or presenilin-1 to test how the level (moderate or high) and the aggregation state (soluble or deposited) of A␤ impacts the proliferation and survival of new hippocampal neurons. Although proliferation and short-term survival of neural progenitors in the hippocampus was unaffected by APP/A␤ overproduction, survival of newborn cells 4 weeks later was dramatically diminished in transgenic mice with Alzheimer's-type amyloid pathology. Phenotypic analysis of the surviving population revealed a specific reduction in newborn neurons. Our data indicate that overproduction of A␤ and the consequent appearance of amyloid plaques cause an overall reduction in the number of adult-generated hippocampal neurons. Diminished capacity for hippocampal neuron replacement may contribute to the cognitive decline observed in these mice.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…2 and 4). Notably, impaired neurogenesis, and specifically the survival and differentiation of neuronal progenitors, have been reported in mouse models of AD [230,231]. Thus, the activation of differentiation programs (neuroD1, bdnf) in pathological brains might be a promising strategy in AD.…”

Firing properties of entorhinal cortex neurons and early alterations in an Alzheimer's disease transgenic model

“…Finally, a recent work demonstrated that the FCs LEC to DG projecting neurons form a major input to the new born neurons of this hippocampal area [50]. Alterations of their firing patterns during early AD symptomatology could contribute to altered neurogenesis [49] and the development of cognitive deficits [9].…”

Neural stem cells: mechanisms and modeling

“…An agedependent decrease in SGZ proliferation was also observed in mice transgenic for human V717F mutant APP, a model of AD with age-dependent accumulation of Aβ42-containing plaques (Donovan et al, 2006). Impaired neuronal differentiation of NPCs was also confirmed in transgenic mice coexpressing two or three mutated genes of APP and PS1 (Verret et al, 2007;Zhang et al, 2007;Rodríguez et al, 2008;Demars et al, 2010). Nevertheless, conflicting observations have been obtained from PDGF-APPswe,ind mice (J20), which express the Swedish and Indiana APP mutations of APP.…”