Abstract:
:Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Koller EJ,Gonzalez De La Cruz E,Machula T,Ibanez KR,Lin WL,Williams T,Riffe CJ,Ryu D,Strang KH,Liu X,Janus C,Golde TE,Dickson D,Giasson BI,Chakrabarty Pdoi
10.1093/hmg/ddz151subject
Has Abstractpub_date
2019-10-01 00:00:00pages
3255-3269issue
19eissn
0964-6906issn
1460-2083pii
5526800journal_volume
28pub_type
杂志文章abstract::Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the first exon of the HD gene, which results in a toxic polyglutamine stretch within huntingtin, the protein it encodes. Understanding the normal function of this essential protein is vital to u...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl467
更新日期:2007-02-15 00:00:00
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pub_type: 杂志文章
doi:10.1093/hmg/9.13.2009
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pub_type: 杂志文章,评审
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更新日期:2013-03-01 00:00:00
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更新日期:2010-02-01 00:00:00
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journal_title:Human molecular genetics
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pub_type: 临床试验,杂志文章
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