Faculty Opinions recommendation of Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes.

The amyloid cascade hypothesis proposes that amyloid beta (Abeta) 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 Abeta 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 Abeta, and 32.3% were positive for p-tau; Abeta 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 Abeta fluorescence was significantly lower in the entorhinal cortex and hippocampus relative to neocortical regions (P = 0.0003). Synaptic Abeta and p-tau fluorescence was significantly correlated (r = 0.683, P < 0.004), and dual-labeling experiments demonstrated that 24.1% of Abeta-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 Abeta levels measured by flow cytometry and oligomeric Abeta species (P < 0.0001). These results showing overlapping Abeta 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. PMID: 18467692 Funding information This work was supported by: NIA NIH HHS, United States Grant ID: R01 AG018879 NIA NIH HHS, United States Grant ID: AG18879 NCI NIH HHS, United States Grant ID: CA 16042 NINDS NIH HHS, United States Grant ID: NS43946 NIAID NIH HHS, United States Grant ID: P30 AI028697 NCI NIH HHS, United States Grant ID: P30 CA016042 NIA NIH HHS, United States Grant ID: P50 AG016570 NIA NIH HHS, United States Grant ID: P50 AG 16570 NIAID NIH HHS, United States Grant ID: AI 28697 NIA NIH HHS, United States Grant ID: 050 AG05142 NINDS NIH HHS, United States Grant ID: R01 NS043946 NIA NIH HHS, United States Grant ID: P50 AG005142 NIA NIH HHS, United States Grant ID: 5AG016570 More Less keyboard_arrow_down