DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive cognitive impairments, most notably memory loss. AD is characterized by neuronal loss and by accumulation of protein deposits (plaques) and neurofibrillary tangles in many brain regions including the hippocampus, a region critical for many forms of learning and memory. The build-up of beta-amyloid peptides, a major component of plaques, is thought to be a causal factor in the cognitive impairments associated with AD, but the physiological effects of beta-amyloid accumulation that would cause these impairments are poorly understood. Our long-term objective is to define physiological mechanisms by which beta-amyloids impair cognition, so that therapies may be developed to protect these mechanisms and thereby limit the damage caused by AD. Recently, several transgenic mouse models for AD have been developed. One of these models, a mouse line with mutations in both amyloid precursor protein (APR) and presenilin-1 (PS-1), has a robust and rapid increase in the levels of beta-amyloids, without formation of tangles or neuronal loss. Hippocampal synaptic function in APP/PS-1 mice is impaired, with early defects in long-term synaptic plasticity and later defects in basal synaptic function. However, the mechanisms underlying these defects remain unknown. In the proposed research, we will identify mechanisms underlying the defects in synaptic function in APP/PS-1 mice. Synaptic properties will be compared in hippocampal slices from APP/PS-1 mice and wild- type littermates, using field potential recordings and whole-cell patch clamp recordings. Two specific aims will be addressed. First, we will identify the synaptic mechanisms that are impaired in these mice during early defects in long-term plasticity, and during late defects in basal synaptic transmission. Second, we will determine whether these defects are caused by the accumulation of beta-amyloids. The proposed research will identify the mechanisms by which APP/PS-1 mutations lead to impaired synaptic function in the hippocampus. Project relevance: The proposed research will identify mechanisms underlying synaptic defects caused by accumulation of beta-amyloids, which is thought to be a major factor in the cognitive impairments in AD.
|Effective start/end date||7/15/07 → 5/31/09|
- National Institutes of Health: $69,300.00
- National Institutes of Health: $67,914.00
Amyloid beta-Protein Precursor
mouse presenilin 1