期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 172, 期 6, 页码 1683-1692出版社
AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.2353/ajpath.2008.070829
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资金
- NCI NIH HHS [CA 16042, P30 CA016042] Funding Source: Medline
- NIAID NIH HHS [P30 AI028697, AI 28697] Funding Source: Medline
- NIA NIH HHS [R01 AG018879, AG18879, P50 AG 16570, 5AG016570, P50 AG016570, 050 AG05142, P50 AG005142] Funding Source: Medline
- NINDS NIH HHS [R01 NS043946, NS43946] Funding Source: Medline
The amyloid cascade hypothesis proposes that amyloid beta (A beta) 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 A beta 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 A beta, and 32.3% were positive for p-tau; A beta 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 A beta fluorescence was significantly lower in the entorbinal cortex and hippocampus relative to neocortical regions (P = 0.0003). Synaptic A beta and p-tau fluorescence was significantly correlated (r = 0.683, P < 0.004), and dual-labeling experiments demonstrated that 24.1% of A beta-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 A beta levels measured by flow cytometry and oligomeric A beta species (P < 0.0001). These results showing overlapping A beta 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.
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