Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation
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RESEARCH
Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation Aleksandra M. Wojtas1,3, Yari Carlomagno2, Jonathon P. Sens1,3, Silvia S. Kang2, Tanner D. Jensen1, Aishe Kurti1, Kelsey E. Baker1, Taylor J. Berry1, Virginia R. Phillips2, Monica Casey Castanedes2, Ayesha Awan1, Michael DeTure2, Cristhoper H. Fernandez De Castro2, Ariston L. Librero2, Mei Yue2, Lillian Daughrity2, Karen R. Jansen‑West2, Casey N. Cook2,3, Dennis W. Dickson2,3, Leonard Petrucelli2,3 and John D. Fryer1,3*
Abstract The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer’s disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD. Keywords: Clusterin, Alzheimer’s disease, Tauopathy, Tau
Introduction Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by deposition of amyloid-β (Aβ) peptide as parenchymal plaques [7] and aggregation of hyperphosphorylated protein tau as neurofibrillary tangles (NFTs) [8]. Aberrant tau accumulation is also a pathological hallmark of other neurodegenerative disorders, collectively known as primary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and frontotemporal dementia with parkinsonisms linked to chromosome 17 (FTDP-17), in which amyloid pathology is not usually observed [23]. Human tauopathies are often classified based on the presence of different tau isoforms that contain three or four carboxy-terminal *Correspondence: [email protected] 1 Department of Neuroscience, Mayo Clinic, Collaborative Research Building CR03‑010 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA Full list of author information is available at the end of the article
repeat domains in the tau aggregates, including 3R (PiD), 4R (PSP, CBD), and 3R + 4R (AD) [12, 23]. Given that tau accumulation strongly correlates with neuronal dysfunction and cognitive impairment in AD and other tauopathies [1, 11], identifying factors that regulate tau aggregation in the brain is critical. Compelling evidence implicates the clusterin (CLU) gene in AD pathophysiology. Several large-scale genomewide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) at the CLU locus that are significantly associated with altered AD risk [9, 13]. In addition, levels of CLU (also known as apolipoprotein J, apoJ) have b
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