Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease

Tingxiang Yan, Luwen Wang, Ju Gao, Sandra L. Siedlak, Mikayla L. Huntley, Pichet Termsarasab, George Perry, Shu G. Chen, Xinglong Wang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Original languageEnglish (US)
Pages (from-to)157-165
Number of pages9
JournalJournal of Alzheimer's disease : JAD
Volume63
Issue number1
DOIs
StatePublished - 2018
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • dystrophic neurites
  • granulovacuolar degeneration
  • neurofibrillary tangles
  • neuropil threads
  • phosphorylated Rab10
  • senile plaques

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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