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Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2.

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.

SUBMITTER: Dhaliwal J

PROVIDER: S-EPMC6299003 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2.

Dhaliwal Jagroop J Kannangara Timal S TS Vaculik Michael M Xue Yingben Y Kumar Keren L KL Maione Amanda A Béïque Jean-Claude JC Shen Jie J Lagace Diane C DC

Scientific reports 20181218 1

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 pr ...[more]

PMID: 30560948

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Project description:Temporal lobe epilepsy (TLE) is the commonest type of focal epilepsy in adult humans, and hippocampal sclerosis (HS) is the main pathological finding in this type of epilepsy. In refractory TLE, patients are indicated for unilateral resection of the affected hippocampus by a surgical procedure called hippocampectomy which generally does not cause any cognitive impairment. Once adult hippocampus is a region of endogenous neurogenesis, even in elderly people, we have hypothesized that a compensatory increase in hippocampal neurogenesis might occur in the remaining hippocampus after unilateral hippocampectomy. To test this hypothesis, we performed unilateral hippocampectomy in adult Wistar rats, which were perfused at 15 (G15) and 30 (G30) days post-surgery. Eighteen Wistar rats were randomly distributed in the following experimental groups: control (no surgery, N = 6), G15 (N = 6), and G30 (N = 6). Adjacent cortex and hippocampus of the left hemisphere were completely removed. Behavioral procedures were performed to address possible cognitive impairments. Brains were collected and fixed from animals belonging to all experimental groups. Gross histopathology was performed using thionine staining. Neuroblasts and mature neurons were immunolabeled using anti-doublecortin (DCX) and anti-NeuN antibodies, respectively. Numbers of DCX and NeuN positive cells were quantified for all experimental groups. Animals submitted to hippocampectomy did not present any cognitive impairment as evaluated by eight-arm radial maze behavioral test. The remaining hippocampus presented a higher number of DCX positive cells compared to control (p < 0.001, ANOVA-Tukey) at both G15 and G30. A higher number of NeuN positive cells were present in the granular layer of dentate gyrus at G30 compared to control and G15 (p < 0.001, ANOVA-Tukey). The data suggest that unilateral hippocampectomy induces compensatory neurogenic effect in the contralateral hippocampus. This may underlie the reported absence of significant cognitive impairment and parallels the findings in human patients submitted to unilateral hippocampectomy to treat refractory TLE.

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Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2.

Publications

Adult hippocampal neurogenesis occurs in the absence of Presenilin 1 and Presenilin 2.

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