Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy

被引：28

作者：

You, Yingjian ^{[1
,2
]}

Perkins, Abigail ^{[1
,2
]}

Cisternas, Pablo ^{[1
,2
]}

Munoz, Braulio ^{[1
,3
]}

Taylor, Xavier ^{[1
,2
]}

You, Yanwen ^{[1
,2
]}

Garringer, Holly J. ^{[4
,5
]}

Oblak, Adrian L. ^{[1
,6
]}

Atwood, Brady K. ^{[1
,3
,7
]}

Vidal, Ruben ^{[1
,4
,5
]}

Lasagna-Reeves, Cristian A. ^{[1
,2
,8
]}

机构：

[1] Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN 46202 USA

[3] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA

[4] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA

[5] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA

[6] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA

[7] Indiana Univ Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA

[8] Indiana Univ Sch Med, Stark Neurosci Res Inst, Neurosci Res Bldg 214G,320 West 15th St, Indianapolis, IN 46202 USA

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2019年 / 7卷 / 1期

关键词：

Cerebral amyloid angiopathy; Tau oligomers; ADan oligomers; Vascular amyloid; Tau downregulation; Neurodegeneration; STRAUSSLER-SCHEINKER DISEASE; ALZHEIMERS-DISEASE; NEUROFIBRILLARY TANGLES; FAMILIAL BRITISH; ISCHEMIC-STROKE; TRANSGENIC MICE; MOUSE MODEL; BETA; PATHOLOGY; DEPOSITION;

D O I：

10.1186/s40478-019-0680-z

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of A, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis is accompanied by significant tau pathology. However, the contribution of tau to neurodegeneration associated to CAA remains to be determined. We used a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature, to characterize the contribution of tau to neurodegeneration associated to CAA. We performed histological and biochemical assays to establish tau modifications associated with CAA in conjunction with cell-based and electrophysiological assays to determine the role of tau in the synaptic dysfunction associated with ADan. We demonstrated that ADan aggregates induced hyperphosphorylation and misfolding of tau. Moreover, in a mouse model for CAA, we observed tau oligomers closely associated to astrocytes in the vicinity of vascular amyloid deposits. We finally determined that the absence of tau prevents synaptic dysfunction induced by ADan oligomers. In addition to demonstrating the effect of ADan amyloid on tau misfolding, our results provide compelling evidence of the role of tau in neurodegeneration associated with ADan-CAA and suggest that decreasing tau levels could be a feasible approach for the treatment of CAA.

引用

页数：15