Memory Impairment, Alzheimer\u27s Disease, And The Role Of Signal Transduction Mechanisms

MEMORY IMPAIRMENT, ALZHEIMER\u27S DISEASE, AND THE ROLE OF SIGNAL TRANSDUCTION MECHANISMS Valerie A. Flores (sponsored by Stephen M. Strittmatter). Section of Cellular Neuroscience, Department of Neurology, Yale University, School of Medicine, New Haven, CT. Alzheimer\u27s disease (AD) is the most common form of dementia plaguing older individuals. It is a progressive disorder that causes abnormalities in cognition, behavior, and functionality. Clinically, it is characterized by a slow development of cognitive impairments, with learning and memory the most severely impaired. The distinguishing pathologic features of AD include beta amyloid (Aβ) plaques and tau neurofibrillary tangles. Soluble Aβ is largely implicated in the cognitive decline of AD. Importantly, levels of soluble Aβ correlate with the extent of cognitive dysfunction and synaptic loss. Dendritic spines, located at postsynaptic sites, mediate synaptic plasticity and are targeted by Aβ oligomers. p21 activated kinases (PAKs) and cofilin protein, both of which are involved in regulating dendritic spine dynamics, have demonstrated altered activity in AD--aberrant activation of PAK (pPAK) with a paradoxical increase in active (dephosphorylated) cofilin . Cellular prion protein (PrPC) is able to bind to Aβ oligomers, in this way mediating loss of long term potentiation (LTP), which is a function of synaptic plasticity. The aim of this study was to first identify an alteration in PAK and cofilin activity in the presence of PrPC in APPswe/ Psen1ΔE9 transgenic mice, which model AD. The second aim was to examine whether, PAK and cofilin activity in APPswe/ Psen1ΔE9 mice lacking PrPCis altered. It was hypothesized that in APPswe/ Psen1ΔE9 mice on the Prnp-/- background, active PAK and phosphorylated (inactive) cofilin levels would return to WT levels. Immunoblot assays were utilized in this study, with statistical analysis carried out with Student\u27s t-tests. There was a minor phenotype for pPAK levels in the AD model mice, and it appeared to be PrP-dependent, however no concomitant change in cofilin levels was found. Statistically, there was a trend toward recovery of pPAK in the AD model with Prnp deletion. There was no statistically significant difference of cofilin in the transgenic model for PrP-dependence could not be tested. In the future, a similar analysis with a different transgenic mouse model may provide more robust changes in PAK and cofilin and thereby further insight into the interaction between Aβ oligomers and cellular PrP, and their affects on synaptic plasticity