Affecting approximately 3 million U.S. Americans and the number is growing as longevity increases; Alzheimer's disease (AD) is the most common of the tragically debilitating senile dementia's. AD is characterized by a decline in cognitive abilities, particularly the acquisition and retrieval of memories. The disease is progressive, affecting mental function to the point of preventing the ability to carry out activities of daily living. In the late stage of AD, patients have profound dementia and are mute, incontinent and bedridden. In AD, there is selective damage to nerve cells within neural circuits that are critical for cognition and memory, including the hippocampus, amygdala, basal forebrain cholinergic system, monoaminergic systems and neocortex. Damage to these brain regions begins with the accumulation of intracellular neurofibrillary tangles (NFTs) and dystrophic neurites surrounding amyloid senile plaques. Amyloid senile plaque number in the neocortex is the primary criterion for the post-mortem diagnosis of AD. A major component of senile plaques is a class of approximately 4 kD amyloid (Abeta) peptides, particularly Abeta42 and Abeta43 (Abeta42(43)). Abeta peptides act as extracellular signaling molecules, affecting some cells, including neurons, by activating the p42/44 MAPK signal transduction pathway. p42 MAPK activity is necessary for the induction of hippocampal LTP, an in vitro model of synaptic plasticity and learning and memory. Since AD is marked by an increased burden of extracellular Abeta peptide and impairments in learning and memory, it is postulated that chronic Abeta stimulation of the p42 MAPK signaling pathway leads to impairment of hippocampus-dependent synaptic plasticity in AD. A transgenic mouse model of AD, in which increased production of Abeta is a consequence of transgene expression, exhibits age-related impairment in hippocampal synaptic plasticity and hippocampus-dependent learning and memory.
The specific aims of this proposal are directed toward testing the hypothesis that chronic exposure of hippocampal neurons to Abeta peptide causes derangement of p42 MAPK signaling and underlies deficits in hippocampal synaptic plasticity and hippocampus-dependent learning and memory in a mouse model of AD.
These aims will be achieved through biochemical assay of the p42 MAPK signal transduction pathway in the hippocampi of these mice under unstimulated (basal) conditions and following LTP tetani and hippocampus-dependent learning.
