Senior Scholar Award in Aging
Sangram S. Sisodia, Ph. D.
University of Chicago

Molecular Determinants of Hippocampal Neuroplasticity in a Mouse Model of b-Amyloid Deposition.

The elderly are the most rapidly growing segment of the population, and Alzheimer’s disease (AD) is the most common type of dementia in this age group. Cognitive decline, memory impairments and decline in verbal episodic memory, the earliest signs of incipient Alzheimer's disease (AD), are the result of disruptions of neural circuits and neuronal loss in the hippocampus. It has been suggested that hippocampal vulnerability is the result of compromised neuroplasticity, a term that refers to the ongoing process of synaptic and dendritic remodeling, axonal sprouting, and long-term potentiation (LTP).

Our laboratory has focused on the mechanism(s) by which mutant genes encoding the amyloid precursor protein (APP) or presenilins (PS1 and PS2) cause early-onset familial forms of AD. To this end, we have generated transgenic mice that coexpress FAD-linked mutant APP and PS1. These animals exhibit Ab deposits in the in the hippocampal formation and we now propose to modulate hippocampal neuroplasticity by altering environmental “experience”. For example, environmental “enrichment” (in the form of social or inanimate stimulation), or running, induces experience-dependent increases in hippocampal thickness, dendritic arborization, neurogenesis, neuronal survival, enhanced long-term potentiation (LTP) and improved spatial memory in mice. On the other hand, environmental “stress” induces secretion of glucocorticoids and adrenal steroids, and these agents perturb hippocampal structure and function, including: disruption of learning and memory-related enhancement of long term depression (LTD); inhibition of dentate neurogenesis; and atrophy of neuronal processes.

Despite this body of evidence that “experience” has a significant impact on hippocampal neuroplasticity, information pertaining to the effects of these manipulations on gene and protein expression in the hippocampus has not emerged. Moreover, we argue that the transgenic mice with Ab deposition offers an attractive model to examine amyloid- and age-associated effects on neurogenesis, hippocampal physiology and gene expression within the hippocampus. To identify alterations in mRNA and polypeptide expression, we will employ DNA microarrays in parallel with proteomic strategies, respectively, in the hippocampus of nontransgenic and transgenic mice subject to environmental manipulations. To validate functions for a subset of newly-identified molecules in “experience”-dependent hippocampal synaptic plasticity, we will generate mice mice harboring alleles that can be conditionally ablated [using CamKIIa-cre transgenes] or regulated [as a CamKIIa-rtTA transgene] for behavioral and electrophysiological studies. These efforts should provide a broad, unbiased view of hippocampal responses as a function of environmental “experience”. This information will be critical for formulating hypotheses relevant to understanding the mechanisms of neuronal vulnerability in the hippocampus as a function of aging and AD, and I anticipate that new molecules identified in the molecular screens will offer molecular targets for enhancement of memory processes in the elderly.

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