BIOLOGY OF ALZHEIMER AMYLOID IN NEURONS

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DESCRIPTION (provided by applicant): Beta-amyloid is a major constituent of the plaques found in the brains of patients afflicted by Alzheimer's disease and reduction in beta-amyloid is currently a major target of therapeutic strategies for the disease. We reported electron microscopy studies to better define the subcellular localization of beta-amyloid in the brain and to determine how plaques form in a well-established transgenic mouse model of beta-amyloidosis. We found that beta-amyloid localized especially to small intracellular organelles, called multivesicular bodies, and smaller vesicles, and that this beta-amyloid accumulates with aging within Alzheimer's disease vulnerable neurons within these organelles until associated morphological alterations appear, especially within distal nerve cell processes and synaptic compartments. Multivesicular bodies are currently being actively studied for their role in recycling and degradation of among others, important membrane receptors, and for their transport along axons of vital cargo proteins, including nerve growth factors and their receptors. Aberrant protein accumulation has become a common theme in neurodegenerative diseases and we propose biological and pathological studies to explore the accumulation and modulation of beta-amyloid in multivesicular bodies within neurons. Specifically, we hypothesize that accumulating beta-amyloid may cause alterations in recycling and/or degradation of important synaptic receptors, in the ubiquitin proteasome system and/or in retrograde transport within neurites. In addition, we hypothesize that our preliminary evidence on synaptic activity reducing intraneuronal beta-amyloid provides a potential explanation for an emerging paradox in the field relating to elevation of beta-amyloid secretion with synaptic activity. A better understanding of beta-amyloid accumulation in multivesicular bodies within neurons, which are associated with early beta-amyloid related changes with Alzheimer disease pathogenesis, may be important in developing more effective treatments for Alzheimer's disease.