Format

Send to

Choose Destination
Acta Neuropathol Commun. 2019 Feb 26;7(1):26. doi: 10.1186/s40478-019-0680-z.

Tau as a mediator of neurotoxicity associated to cerebral amyloid angiopathy.

Author information

1
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
2
Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
3
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
4
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
5
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
6
Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
7
Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
8
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. clasagna@iu.edu.
9
Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. clasagna@iu.edu.
10
Indiana University School of Medicine, The Stark Neurosciences Research Institute, Neurosciences Research Building 214G, 320 West 15th Street, Indianapolis, IN, 46202, USA. clasagna@iu.edu.

Abstract

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 Aβ, 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.

KEYWORDS:

ADan oligomers; Cerebral amyloid angiopathy; Neurodegeneration; Tau downregulation; Tau oligomers; Vascular amyloid

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center