Co-Localization of Amyloid Beta and Tau Pathology in Alzheimer's Disease Synaptosomes

The amyloid cascade hypothesis proposes that amyloid β (Aβ) pathology precedes and induces tau pathology, but the neuropathological connection between these two lesions has not been demonstrated. We examined the regional distribution and co-localization of Aβ and phosphorylated tau (p-tau) in synaptic terminals of Alzheimer's disease brains. To quantitatively examine large populations of individual synaptic terminals, flow cytometry was used to analyze synaptosomes prepared from cryopreserved Alzheimer's disease tissue. An average 68.4% of synaptic terminals in the Alzheimer's disease cohort (n = 11) were positive for Aβ, and 32.3% were positive for p-tau; Aβ and p-tau fluorescence was lowest in cerebellum. In contrast to synaptic p-tau, which was highest in the entorhinal cortex and hippocampus (P = 0.004), synaptic Aβ fluorescence was significantly lower in the entorhinal cortex and hippocampus relative to neocortical regions (P = 0.0003). Synaptic Aβ and p-tau fluorescence was significantly correlated (r = 0.683, P < 0.004), and dual-labeling experiments demonstrated that 24.1% of Aβ-positive terminals were also positive for p-tau, with the highest fraction of dual labeling (39.3%) in the earliest affected region, the entorhinal cortex. Western blotting experiments show a significant correlation between synaptic Aβ levels measured by flow cytometry and oligomeric Aβ species (P < 0.0001). These results showing overlapping Aβ and tau pathology are consistent with a model in which both synaptic loss and dysfunction are linked to a synaptic amyloid cascade within the synaptic compartment.