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P3‐300: Phosphorylated TAU and Alpha‐Synuclein Accumulation in Familial Granulin Mutation Cases
Author(s) -
Hosokawa Masato,
Arai Tetsuaki,
Kondo Hiromi,
Serrano Geidy E.,
Beach Thomas G.,
Hasegawa Masato,
Akiyama Haruhiko
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1964
Subject(s) - frontotemporal lobar degeneration , tauopathy , biology , neurodegeneration , mutation , pathology , alpha synuclein , corticobasal degeneration , tau protein , genetically modified mouse , alzheimer's disease , frontotemporal dementia , microbiology and biotechnology , parkinson's disease , transgene , disease , genetics , progressive supranuclear palsy , medicine , dementia , gene
Background:Granulin (GRN) mutations were identified in patients with familial frontotemporal lobar degeneration (FTLD) with ubiquitin pathology in 2006 studies. GRN transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. GRN mutations were first found in tau-negative FTLD patients, however, recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer’s disease and corticobasal degeneration. Moreover, PGRN reduction in tau transgenic mice is associated with increasing tau phosphorylation and accumulation. Methods: To investigate the influence of a decline in PGRN protein on other forms of neurodegenerativerelated protein accumulation, human GRN mutation cases were investigated by histochemical and biochemical analyses. Results: The results showed neuronal and glial tau accumulation in all cases analyzed. Massive neuronal tau staining revealed pretangle forms and glial tau in both astrocytes and oligodendrocytes. Furthermore, phosphorylated alpha-synuclein-positive structures were also found in oligodendrocytes and the neuropil. Immunoblot analysis of fresh frozen brain tissues revealed that tau protein was present in the sarkosyl-insoluble fraction, which was composed of threeand four-repeat tau isoforms, resembling Alzheimer’s disease. Conclusions:Our data suggest that PGRN reduction might be the cause of neuronoglial multiple proteinopathies, including TDP-43 proteinopathy, tauopathy and alpha-synucleinopathy, due to the accelerating accumulation of abnormal proteins. P3-301 WHICH NEUROPATHOLOGICAL MARKER CORRELATES BEST WITH ANTE-MORTEM COGNITIVE SYMPTOMS? Arnaud Francois, Cyntia Tremblay, Charlotte Delay, Milene Vandal, David A. Bennett, Frederic Calon, CHU de Quebec, Quebec City, QC, Canada; CHU de Quebec, Quebec, QC, Canada; INSERMU1167, Lilles, France; 4 Pharmacy, LAVAL University, Quebec City, QC, Canada; 5 Rush Alzheimer’s Disease Center, Chicago, IL, USA; Faculty of Pharmacy, Universit e Laval, Quebec, QC, Canada. Contact e-mail: frederic.calon@ crchul.ulaval.ca