Rab GTPase Proteins in Tauopathy (5236)

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Objective: To elucidate the role of specific Rab GTPase proteins, Rab8a or Rab35, in tau accumulation and aggregate formation.

Background: Alzheimer disease (AD) is characterized by the abnormal deposition of amyloid-beta (Aβ) plaques and tau tangles in neurons and glia. Although Aβ correlates well with disease, abnormal, tau accumulation is thought to be a major factor contributing to neurodegeneration in AD. Increasing data indicate that that specific Rab proteins malfunction in affected brain regions in AD. Nearly 70 Rab GTPase proteins have been identified in humans. Rab proteins play an important role in intracellular trafficking, endocytosis, and exocytosis/secretion; and may contribute to clearance of abnormally aggregated proteins including tau. Altered Rab function may be a precursor to tau protein accumulation, aggregation, and associated AD and AD-related pathology. Among several Rab proteins, both Rab8a and Rab35 have emerging roles in Parkinson disease (PD) and AD pathophysiology. In PD Rab35 levels are high in serum and in brain regions affected by disease, implying a role in disease pathology.

Design/Methods: Human neuroglioma H4 cells were co-transfected with 4R0N wild type or self-aggregating mutant tau[P301L/S320F] and Rab8a/35 (and functional mutants). Total tau pathological phospho-tau levels were analyzed by Western blot, and aggregate formation with ThioS. The results were compared to a proteomics dataset and Rab expression analyses in postmortem tissue from from AD, PSP (progressive supranuclear palsy) and CBD (corticobasal degeneration).

Results: In contrast to PD, Rab35 expression is decreased in postmortem brain tissues from AD, PSP and CBD, whereas Rab8a appears increased, especially in white mater. Both Rab8a and Rab35 overexpression in H4 cells resulted in a marked reduction of total and phosphor-tau. Further, Rab8a and Rab35 reduced ThioS positive tau inclusions in vitro.

Conclusions: These data provide the first evidence that Rab8a and Rab35 may regulate tau levels and associated pathology.



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