Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice

Wu, Pu; Shen, Qian; Dong, Suzhen; Xu, Zhiliang; Tsien, Joe Z.; Hu, Yinghe

doi:10.1016/j.neurobiolaging.2007.03.028

« Previous Next »Neurobiology of Aging
Volume 29, Issue 10 , Pages 1502-1511, October 2008

Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice

Pu Wu
- Shanghai Institute of Brain Functional Genomics, MOE & STCSM Key Lab of Brain Functional Genomics, East China Normal University, Shanghai 200062, China
Qian Shen
- Shanghai Institute of Brain Functional Genomics, MOE & STCSM Key Lab of Brain Functional Genomics, East China Normal University, Shanghai 200062, China
Suzhen Dong
- Shanghai Institute of Brain Functional Genomics, MOE & STCSM Key Lab of Brain Functional Genomics, East China Normal University, Shanghai 200062, China
Zhiliang Xu
- Center for Systems Neurobiology, Departments of Pharmacology and Biomedical Engineering, Boston University, Boston, MA 02118, USA
Joe Z. Tsien
- Center for Systems Neurobiology, Departments of Pharmacology and Biomedical Engineering, Boston University, Boston, MA 02118, USA
Yinghe Hu
- Shanghai Institute of Brain Functional Genomics, MOE & STCSM Key Lab of Brain Functional Genomics, East China Normal University, Shanghai 200062, China
- Corresponding author at: Key Lab of Brain Functional Genomics, MOE & STCSM, Shanghai Institute of Brain Functional Genomics, East China Normal University, 3663 Zhongshan Road N. Shanghai 200062, China. Tel.: +86 21 62603004; fax: +86 21 62601953.

Received 6 October 2006; received in revised form 16 March 2007; accepted 30 March 2007. published online 14 May 2007.

Abstract

Conditional double knockout of presenilin-1 and presenilin-2 (cDKO) in forebrain of mice led to brain atrophy, tau hyperphosphorylation, synaptic dysfunction and cognitive deficit. These brain changes recapitulated most of the neurodegenerative phenotypes of Alzheimer's disease (AD). In this report, we have investigated the effects of 4-month calorie restriction (CR) regimen on different phenotypes in cDKO mice. We found that CR improved novel object recognition and contextual fear conditioning memory in the cDKO mice. Histological and biochemical analysis showed that CR attenuated ventricle enlargement, caspase-3 activation and astrogliosis. In addition, the induction of tau hyperphosphorylation in the cDKO mice was reduced by CR, possibly through reduction of p25 accumulation and aberrant CDK5 activation. Finally, DNA microarray analysis demonstrated that CR could increase the expression of neurogenesis related genes and decrease the expression of inflammation related genes in the hippocampus of cDKO mice. The possible molecular mechanisms of the CR effects on alleviating AD pathogenesis have been discussed.

Keywords: Calorie restriction, Presenilins, Tau hyperphosphorylation, Neurodegeneration, Alzheimer's disease, Microarray