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Abstract
Mutations in the presenilin genes (PS1 and PS2) are a major cause of familial-Alzheimer’s disease (FAD). Presenilins regulate neurogenesis in the developing brain, with loss of PS1 inducing aberrant premature differentiation of neural progenitor cells, and additional loss of PS2 exacerbating this effect. It is unclear, however, whether presenilins are involved in adult neurogenesis, a process that may be impaired in Alzheimer’s disease within the hippocampus. To investigate the requirement of presenilins in adult-generated dentate granule neurons, we examined adult neurogenesis in the PS2−/− adult brain and then employ a retroviral approach to ablate PS1 selectively in dividing progenitor cells of the PS2−/− adult brain. Surprisingly, the in vivo ablation of both presenilins resulted in no defects in the survival and differentiation of adult-generated neurons. There was also no change in the morphology or functional properties of the retroviral-labeled presenilin-null cells, as assessed by dendritic morphology and whole-cell electrophysiology analyses. Furthermore, while FACS analysis showed that stem and progenitor cells express presenilins, inactivation of presenilins from these cells, using a NestinCreERT2 inducible genetic approach, demonstrated no changes in the proliferation, survival, or differentiation of adult-generated cells. Therefore, unlike their significant role in neurogenesis during embryonic development, presenilins are not required for cell-intrinsic regulation of adult hippocampal neurogenesis.
Highlights
Mutations in the Presenilin genes (PS1 and PS2) are the major cause of early onset familial-Alzheimer’s disease (FAD) through a loss-of-function mechanism[1,2]
We examine whether presenilins, a leading contributor to FAD, have a cell autonomous role in hippocampal adult neurogenesis by examining PS2−/− mice and by ablating PS1 and PS2 in neural stem cells (NSCs) and NPCs using two independent models
In the absence of presenilins, NSCs and their progeny demonstrated no significant alterations in stem cell maintenance, proliferation, or differentiation, and showed electrophysiological properties similar to that of naïve adult-generated granule neurons
Summary
Mutations in the Presenilin genes (PS1 and PS2) are the major cause of early onset familial-Alzheimer’s disease (FAD) through a loss-of-function mechanism[1,2]. Adult neurogenesis is a process where neural stem cells (NSCs) and progenitor cells (NPCs) give rise to new neurons in several brain regions, including the subgranular zone (SGZ) of the hippocampus. Alzheimer’s disease (AD) has been reported to compromise adult neurogenesis, with AD-associated molecular players such as presenilins, Notch 1, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), apolipoprotein E (ApoE), and amyloid precursor protein (APP) having either intrinsic, or non-cell autonomous effects, that modulate adult hippocampus neurogenesis[9,10,11,12,13,14,15,16,17]. A knockdown of PS1 in NPCs was reported to be associated with impaired cognitive function[18,19]; there have been no studies testing the requirement of PS1 and PS2 in neural stem cells of the adult brain, nor the possible compensatory contribution of PS28 in the context of adult neurogenesis. Our data provide strong evidence that presenilins are not essential for the cell autonomous regulation of adult hippocampal neurogenesis
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