The presenilin(PS) genes harbor approximately 90% of the identified mutations linked to familial forms of Alzheimer's disease, and the presenilin (PS) proteins are essential components of the γ-secretase complex involved in the proteolytic cleavage of type I receptors, such as Notch and the amyloid precursor protein. Genetic analysis employing cell type-specific conditional knockout technology highlighted the importance of PS in the adult brain, including learning and memory, synaptic function and age-dependent neuronal survival. In the central synapse, PS regulates neurotransmitter release, short- and long-term synaptic plasticity and calcium homeostasis. However, the molecular mechanisms by which PS maintains these essential functions are less clear. Although many γ-secretase substrates have been identified, their physiological relevance is often unclear. The findings that nicastrin and PS conditional knockout mice exhibit similar deficits in memory and age-dependent neurodegeneration are consistent with the notion that γ-secretase-dependent activities of PS are required for the maintenance of memory and neuronal survival, though the γ-secretase physiological substrates, Notch receptors, are not targets of PS in the adult brain. Thus, despite of the intense interest in PS since its identification in 1995, more work is needed to define the molecular and cellular mechanisms by which PS controls brain functions and the dysfunction conferred by disease-causing mutations.

1.
Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S: Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 1997;89:629-639.
2.
Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS: Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 1997;387:288-292.
3.
Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A: Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 1999;13:2801-2810.
4.
Wines-Samuelson M, Shen J: Presenilins in the developing, adult, and aging cerebral cortex. Neuroscientist 2005;11:441-451.
5.
Handler M, Yang X, Shen J: Presenilin-1 regulates neuronal differentiation during neurogenesis. Development 2000;127:2593-2606.
6.
Wines-Samuelson M, Handler M, Shen J: Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons. Dev Biol 2005;277:332-346.
7.
Kim WY, Shen J: Presenilins are required for maintenance of neural stem cells in the developing brain. Mol Neurodegener 2008;3:2.
8.
Beglopoulos V, Shen J: Gene-targeting technologies for the study of neurological disorders. Neuromolecular Med 2004;6:13-30.
9.
Yu H, Saura CA, Choi SY, Sun LD, Yang X, Handler M, Kawarabayashi T, Younkin L, Fedeles B, Wilson MA, Younkin S, Kandel ER, Kirkwood A, Shen J: APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 2001;31:713-726.
10.
Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ 3rd, Kandel ER, Duff K, Kirkwood A, Shen J: Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 2004;42:23-36.
11.
Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Sudhof TC, Shen J: Presenilins are essential for regulating neurotransmitter release. Nature 2009;460:632-636.
12.
Zhang D, Zhang C, Ho A, Kirkwood A, Sudhof TC, Shen J: Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction. J Neurochem 2010;115:1215-1221.
13.
Ho A, Shen J: Presenilins in synaptic function and disease. Trends Mol Med 2011;17:617-624.
14.
Shen J: Impaired neurotransmitter release in Alzheimer's and Parkinson's diseases. Neurodegener Dis 2010;7:80-83.
15.
Saura CA, Chen G, Malkani S, Choi SY, Takahashi RH, Zhang D, Gouras GK, Kirkwood A, Morris RG, Shen J: Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 2005;25:6755-6764.
16.
Beglopoulos V, Sun X, Saura CA, Lemere CA, Kim RD, Shen J: Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem 2004;279:46907-46914.
17.
Wines-Samuelson M, Schulte EC, Smith MJ, Aoki C, Liu X, Kelleher RJ 3rd, Shen J: Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice. PLoS One 2010;5:e10195.
18.
Tabuchi K, Chen G, Sudhof TC, Shen J: Conditional forebrain inactivation of nicastrin causes progressive memory impairment and age-related neurodegeneration. J Neurosci 2009;29:7290-7301.
19.
Haapasalo A, Kovacs DM: The many substrates of presenilin/gamma-secretase. J Alzheimers Dis 2011;25:3-28.
20.
Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA: Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci USA 1999;96:6959-6963.
21.
Zheng J, Watanabe H, Wines-Samuelson M, Zhao H, Gridley T, Kopan R, Shen J: Conditional deletion of Notch1 and Notch2 genes in excitatory neurons of postnatal forebrain does not cause neurodegeneration or reduction of Notch mRNAs and proteins. J Biol Chem 2012;287:20356-20368.
22.
Shen J, Kelleher RJ 3rd: The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci USA 2007;104:403-409.
23.
Heilig EA, Xia W, Shen J, Kelleher RJ 3rd: A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem 2010;285:22350-22359.
24.
Watanabe H, Xia D, Kanekiyo T, Kelleher RJ 3rd, Shen J: Familial frontotemporal dementia-associated presenilin-1 c.548G>T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice. J Neurosci 2012;32:5085-5096.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.