title: Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies.
abstract: Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36-56%) and in DLB (53-60%) than previously reported. Of the TDP-43-positive cases, about 20-30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and alpha-synuclein.
authors.affiliation: Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. arai@prit.go.jp
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonoka
authors.forename: Kazhuhiro
authors.initials: K
authors.lastname: Niizato
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Shuji
authors.initials: S
authors.lastname: Iritani
authors.forename: Mitsumoto
authors.initials: M
authors.lastname: Onaya
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D054022:Cerebrum / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D000077153:Progranulins
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins