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Subcellular Ab Accumulation and Origin of Plaques in Alzheimer's Disease

View Gunnar Gouras' presentation or see related links.

Objective: We have been studying the generation and subcellular localization of Ab in neurons by biochemical and immunocytochemical assays, and more recently have turned to immuno-gold electron microscopy (EM) to determine the more precise localization of Ab peptides and amyloid precursor protein (APP) within neurons of normal brain and to study the earliest site of Ab accumulation and neuropathology with aging in AD mouse models of b-amyloidosis.

Methods: Normal and APP knockout mouse, rat and human biopsy brain tissue were studied by immuno-gold EM for the subcellular site(s) of brain Ab and APP using specific antibodies directed at the C-terminus of Ab40, Ab42 or APP. Tg2576 Swedish FAD mutant APP mice were reported to have increases in brain Ab levels by ELISA months prior to plaque formation. We utilized IP/Western for Ab to confirm these increases, and utilized immuno-EM to determine where in the brain these pre-plaque Ab increases occur. Human AD biopsy tissue was also examined by immuno-gold EM. Results: We have found that especially in AD vulnerable neurons of mouse, rat and human brain, Ab x-42 localizes especially to small endosomal multivesicular bodies (MVBs). Ab42 is also evident in endoplasmic reticulum (ER), TGN and small vesicles. In contrast to Ab42, full-length/C-terminal APP by immuno-EM resides predominantly in the Golgi. In addition to other controls, MVB associated Ab42 was not observed in APP knockout mice. In Tg2576 mice, immuno-gold Ab42 increased within MVBs with aging, especially in distal neuronal processes. Prior to and with Ab plaques, MVB-associated neuronal Ab accumulation was associated with neuropathology in Tg2576 mice and human AD brain.

Conclusions: Our data support the hypothesis that intraneuronal Ab42 accumulation is involved in the earliest neuropathology of AD and appears to be the precursor of Ab plaques.

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Related Links

• Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.