Synaptic Deficits Are Rescued in the p25/Cdk5 Model of Neurodegeneration by the Reduction of β-Secretase (BACE1)

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid beta (A beta) 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 A beta, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of A beta, as well as the APP processing enzyme, beta-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased A beta plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored A beta levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the A beta-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of A beta 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 A beta-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting A beta production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.