Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease
Gorazd B. Stokin, Concepción Lillo, Tomás L. Falzone, Richard G. Brusch, Edward Rockenstein, Stephanie L. Mount, Rema Raman, Peter Davies, Eliezer Masliah, David S. Williams, Lawrence S. B. Goldstein- Multidisciplinary
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-β peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of β-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.