FIGURE 5.

Endosomal “traffic jams” may drive amyloid beta (Aβ) pathology. (A) Schematic of an endosomal “traffic jam” similar to that described for genetic insults to retromer signaling, ⁴⁵ showing an endosome containing amyloid precursor protein (APP) and β secretase trapped in aggregated pS214Tau on a microtubule. (B) A schematic diagram of early stage tau pathology in a dendrite (den), where aggregations of phosphorylated tau (red) on microtubules (green) trap endosomes (blue) and exacerbate the production of Aβ, which is then released into the extracellular space, e.g. after axonal transport. Real examples of aggregated pS214Tau on microtubules trapping endosomes are shown in panels D and E. nuc = nucleus. (C) A schematic diagram of later stage tau pathology, with fibrillated tau in the dendrite and soma now accompanied by extensive autophagic vacuoles (vac), where normal neuronal organelles are now lost, and the cellular engine for Aβ production has deteriorated. A real example of an autophagic vacuole in a dendrite is shown in panel F. (D, E) ImmunoEM of the aged monkey layer III dorsolateral prefrontal cortex (dlPFC) showing early‐stage, soluble pS214Tau (indicated by red arrowheads) aggregating on microtubules in dendrites (den) where it traps enlarged endosomes (pseudocolored in blue, and indicated by blue arrowheads). Aggregations of pS214Tau are often seen near dysmorphic mitochondria (mit), consistent with local calcium dysregulation. Note that the dlPFC is a site of extensive Aβ pathology in sporadic Altzheimer's disease. Interestingly, rhesus monkeys are apoE4 genotype, ⁵² which may increase the numbers of endosomes in this species. ⁵³ Scale bar in B: 200 nm; scale bar in C: 200 nm. (F) With advanced age, pTau‐afflicted dendrites fill with autophagic vacuoles (vac), such as the one seen here in dlPFC, and lose normal organelles, including those needed to generate Aβ. Scale bar in D: 200 nm. Scale bars in D‐F: 200 nm