MECHANISMS OF AMYLOID BETA PEPTIDE-INDUCED NEURONAL DEFICITS

J. David Gladstone Institutes, San Francisco CA

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Abstract

We will study the roles of the amyloid precursor protein (APP) and APP-derived amyloid beta peptides (Abeta) in the pathogenesis of Alzheimer's disease (AD), the most frequent proteopathy of the aging central nervous system. We previously overexpressed wildtype human APP (hAPP[WT]) or familial AD-mutant human APP (hAPP[FAD]) in neurons of transgenic mice. Amyloid deposition in these mice depended on absolute and relative levels of the 42-amino acid form of Abeta (Abeta1-42) and on interactions of this fibrillogenic peptide with other molecules. Synaptic deficits correlated with Abeta levels but not with the deposition of Abeta into amyloid plaques, suggesting a plaque-independent neurotoxicity of Abeta. Expression of apolipoprotein (apo) E3, but not of apoE4, prevented or delayed synaptic loss and memory impairments in hAPP[FAD]/apoE doubly transgenic mice. Aged hAPP[FAD] mice with high Abeta1-42 levels also had losses of cholinergic neurons in the basal forebrain. Recently, we found that behavioral deficits in hAPP[FAD] mice were tightly correlated with reductions in the calcium-binding protein, calbindin-D28 K (CB), in the dentate gyrus. In Aim 1, we will determine why neuronal CB levels in the dentate gyrus are strongly diminished in hAPP[FAD] mice but only minimally in hAPP[WT] mice. We will assess the dependence of CB reductions on the levels of deposited and nondeposited Abeta species and evaluate the role of calcium channels in the CB alterations. In Aim 2, we will examine whether CB reduction plays a critical role in the development of Abeta-induced behavioral deficits. We will correlate CB levels with functional neuronal deficits in hAPP mice and examine whether regulatable overexpression of CB modulates these deficits. In Aim 3, we will characterize the cholinergic deficits in hAPP mice and assess their mechanisms and behavioral consequences. We will study the cholinergic basal forebrain system of these mice, evaluate whether they have deficits in the expression, transport, or release of brain-derived neurotrophic factor, and test whether increasing acetylcholine levels improves their behavioral deficits. In Aim 4, we will examine doubly transgenic mice to be generated in other components of this program to determine if and how the development of Abeta-induced neuronal deficits is modulated by apoE and alpha-synuclein. These studies will shed light on the molecular cascades that lead from the pathogenic assembly of Abeta to functional neurological decline. The proposed experiments follow up on a solid body of preliminary data and actively contribute to the cohesiveness of the program. Their success depends on most, if not all, components of the proposed program.