期刊
ACTA NEUROPATHOLOGICA
卷 139, 期 6, 页码 1045-1070出版社
SPRINGER
DOI: 10.1007/s00401-020-02148-4
关键词
Tauopathy; Aging; P301L mutation; Conformation; Focal pathology; Seeding; Strain ensembles; Transgenic mouse
资金
- Canada Research Chair (Tier 1)
- CIHR [PS148962, GER 163048]
- Alberta Innovates Biosolutions [ABIBS AEP 201600021, 20160023, FP00209618]
- Canada Foundation for Innovation [NIF21633]
- CIHR CGS-M studentship
- NIH [1RF1AG058267, 1RF1AG061797]
- Alzheimer Society of Alberta through the joint Alberta Alzheimer's Research Program [AARP 201700005]
- Northwest Territories through the joint Alberta Alzheimer's Research Program [AARP 201700005]
- Alberta Synergies in Alzheimer's and Related Disorders (SynAD) program - Alzheimer Society of Alberta
- Northwest Territories through their Hope for Tomorrow program
- University Hospital Foundation
- Alberta Innovates [PEX19017]
- University of Alberta
- CONACYT [472481]
Tau protein accumulation is a common denominator of major dementias, but this process is inhomogeneous, even when triggered by the same germline mutation. We considered stochastic misfolding of human tau conformers followed by templated conversion of native monomers as an underlying mechanism and derived sensitive conformational assays to test this concept. Assessments of brains from aged TgTau(P301L) transgenic mice revealed a prodromal state and three distinct signatures for misfolded tau. Frontotemporal lobar degeneration (FTLD)-MAPT-P301L patients with different clinical phenotypes also displayed three signatures, two resembling those found in TgTau(P301L) mice. As physicochemical and cell bioassays confirmed diverse tau strains in the mouse and human brain series, we conclude that evolution of diverse tau conformers is intrinsic to the pathogenesis of this uni-allelic form of tauopathy. In turn, effective therapeutic interventions in FTLD will need to address evolving repertoires of misfolded tau species rather than singular, static molecular targets.
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