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. 2018;63(1):157-165.
doi: 10.3233/JAD-180023.

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

Tingxiang Yan  1 , Luwen Wang  1 , Ju Gao  1 , Sandra L Siedlak  1 , Mikayla L Huntley  1 , Pichet Termsarasab  1 , George Perry  2 , Shu G Chen  1 , Xinglong Wang  1   3
Affiliations

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

Tingxiang Yan et al. J Alzheimers Dis. 2018.

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.

Keywords: Alzheimer’s disease; dystrophic neurites; granulovacuolar degeneration; neurofibrillary tangles; neuropil threads; phosphorylated Rab10; senile plaques.

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Figures

Fig. 1
Fig. 1
Immunocytochemical analysis of pRab10-T73 in a hippocampal section from an AD patient and a normal subject. A) Lesions of NFTs and DNs around SPs (arrowheads) in the CA1 region of an 80-year-old AD patient contain pRab10-T73. B) Higher magnification of the CA1 region of a 67-year-old AD patient shows that in addition to NFTs (marked with asterisk), both GVD (arrows) and neuropil threads could be recognized by the antibody against pRab10-T73. C) In a normal control subject, CA1 neurons display weak pRab10-T73 immunoreactivity. D) Representative enlargements show faint immunoreactivity in some neuronal nuclei.
Fig. 2
Fig. 2
Immunoreactivity of pRab10-T73 is phosphatase sensitive. A) Immunocytochemistry of pRab10-T73 in an untreated section of hippocampus tissue from an 84-year-old AD patient. B) Immunocytochemistry of pRab10-T73 in a serial adjacent tissue section pre-treated with alkaline phosphatase. Landmark vessel is marked with asterisk.
Fig. 3
Fig. 3
Double immunofluorescent staining of pRab10-T73 and phosphorylated tau (AT8) or Aβ (6E10) in a hippocampal section from an AD patient. A) Representative three-dimensional (3D) image showing the presence of pRab10-T73 in NFT-bearing AD pyramidal neurons (arrow). B) Representative 3D image showing pRab10-T73 in DNs containing phosphorylated tau (arrows). C) Representative 3D image showing pRab10-T73 in phosphorylated tau positive neuropil threads (arrows). D) Representative 3D image showing the minimal overlapping between pRab10 -T73 and SPs. The nuclei stained by DAPI are blue.
Fig. 4
Fig. 4
Immunocytochemical analysis of pRab10-T73 in a cortical section from a DS patient and the brainstem of a PSP patient. In serial sections of DS, many of the PHF1-positive NFTs (B) contain pRab10-T73 (A). In serial sections of PSP, a subset of AT8-positive PSP tangles (D) are pRab10-T73 positive (C).
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