Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iA beta), and the mechanism of an age-related increase in iA beta in adult AD-model mouse neurons. A new end-specific antibody for A beta(45) and another for aggregated forms of A beta provide new insight into the composition of iA beta and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iA beta levels containing aggregates of A beta(45) increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iA beta was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized A1z50 tau colocalized with iA beta and rapidly increased following a brief metabolic stress with glutamate. A beta PP-CTF, A beta(45), and aggregated A beta colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iA beta by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long A beta s by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iA beta processing may lead to application of countermeasures to prolong dementia-free health span.