BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology.

Autor: Taga M; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., Petyuk VA; Pacific Northwest National Laboratory, Richland, WA, USA., White C; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., Marsh G; Biogen, 225 Binney St, Cambridge, MA, 02142, USA., Ma Y; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA., Klein HU; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., Connor SM; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., Kroshilina A; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA., Yung CJ; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA., Khairallah A; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA., Olah M; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., Schneider J; Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA., Karhohs K; Imaging Platform, Broad Institute, Cambridge, MA, USA., Carpenter AE; Imaging Platform, Broad Institute, Cambridge, MA, USA., Ransohoff R; Third Rock Ventures, 29 Newbury Street, Suite 301, Boston, MA, 02116, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Bennett DA; Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA., Crotti A; Biogen, 225 Binney St, Cambridge, MA, 02142, USA., Bradshaw EM; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA., De Jager PL; Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA. pld2115@cumc.columbia.edu.; Cell Circuits Program, Broad Institute, Cambridge, MA, USA. pld2115@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Molecular neurodegeneration [Mol Neurodegener] 2020 Jul 29; Vol. 15 (1), pp. 44. Date of Electronic Publication: 2020 Jul 29.
DOI: 10.1186/s13024-020-00387-3
Abstrakt: Background: Identified as an Alzheimer's disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear.
Methods: Utilizing antibodies targeting specific BIN1 epitopes in human post-mortem tissue and analyzing mRNA expression data from purified microglia, we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed.
Results: Peptides contained in exon 7 of BIN1's N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles. Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant.
Conclusions: Exploring the molecular mechanisms of specific BIN1 isoforms expressed by astrocytes may open new avenues for modulating the accumulation of Tau pathology in AD.
Databáze: MEDLINE
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