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 (iAbeta), and the mechanism of an age-related increase in iAbeta in adult AD-model mouse neurons. A new end-specific antibody for Abeta45 and another for aggregated forms of Abeta provide new insight into the composition of iAbeta and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAbeta levels containing aggregates of Abeta45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAbeta 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 Alz50 tau colocalized with iAbeta and rapidly increased following a brief metabolic stress with glutamate. AbetaPP-CTF, Abeta45, and aggregated Abeta colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAbeta by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Abetas by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAbeta processing may lead to application of countermeasures to prolong dementia-free health span.