Format

Send to

Choose Destination
See comment in PubMed Commons below
J Neurosci. 2011 Nov 2;31(44):15751-6. doi: 10.1523/JNEUROSCI.3588-11.2011.

Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1).

Author information

1
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.

PMID:
22049418
PMCID:
PMC3248793
DOI:
10.1523/JNEUROSCI.3588-11.2011
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center