PMID:25429133

Citation	Watanabe, H, Iqbal, M, Zheng, J, Wines-Samuelson, M and Shen, J (2014) Partial loss of presenilin impairs age-dependent neuronal survival in the cerebral cortex. J. Neurosci. 34:15912-22
Abstract	Mutations in the presenilin (PSEN1 and PSEN2) genes are linked to familial Alzheimer's disease (AD) and cause loss of its essential function. Complete inactivation of presenilins in excitatory neurons of the adult mouse cerebral cortex results in progressive memory impairment and age-dependent neurodegeneration, recapitulating key features of AD. In this study, we examine the effects of varying presenilin dosage on cortical neuron survival by generating presenilin-1 conditional knock-out (PS1 cKO) mice carrying two, one, or zero copies of the PS2 gene. We found that PS1 cKO;PS2(+/-) mice at 16 months exhibit marked neurodegeneration in the cerebral cortex with ∼17% reduction of cortical volume and neuron number, as well as astrogliosis and microgliosis compared with ∼50% reduction of cortical volume and neuron number in PS1 cKO;PS2(-/-) mice. Moreover, there are more apoptotic neurons labeled by activated caspase-3 immunoreactivity and TUNEL assay in PS1 cKO;PS2(+/-) mice at 16 months, whereas apoptotic neurons are increased in the PS1 cKO;PS2(-/-) cerebral cortex at 4 months. The accumulation of the C-terminal fragments of the amyloid precursor protein is inversely correlated with PS dosage. Interestingly, levels of PS2 are higher in the cerebral cortex of PS1 cKO mice, suggesting a compensatory upregulation that may provide protection against neurodegeneration in these mice. Together, our findings show that partial to complete loss of presenilin activity causes progressively more severe neurodegeneration in the mouse cerebral cortex during aging, suggesting that impaired presenilin function by PSEN mutations may lead to neurodegeneration and dementia in AD.
Links	PubMed PMC4244465 Online version:10.1523/JNEUROSCI.3261-14.2014
Keywords	Aging/metabolism; Aging/pathology; Animals; Cell Survival/physiology; Cerebral Cortex/metabolism; Cerebral Cortex/pathology; Female; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons/metabolism; Neurons/pathology; Presenilin-1/deficiency; Presenilin-2/deficiency
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PSN2		GO:0030900: forebrain development	ECO:0000314:		P		The paper and experiment suggests necessary information on forebrain development	complete CACAO 10612
MOUSE:PSN2		GO:0070050: neuron cellular homeostasis	ECO:0000316:	UniProtKB:P49769	P		Figure 1 C-E brain weight, cortical volume, and cortical neuron (x10^6 cells) is decreased in PS1 cKO;PS2 -/- mice as compared to PS1 cKO;PS2 +/- mice after 16 months.	complete CACAO 10710
MOUSE:PSN2	involved_in	GO:0070050: neuron cellular homeostasis	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P49769	P		Seeded From UniProt	complete

References

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