Tau reduction in aged mice does not impact Microangiopathy
Rachel E Bennett1, Miwei Hu2, Analiese Fernandes2
1Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA. rebennett@mgh.harvard.edu.
Acta Neuropathologica Communications
|August 20, 2020
Summary
Soluble tau protein accumulates at the blood-brain barrier in Alzheimer's disease (AD) models. Reducing tau levels did not resolve existing microvascular damage, suggesting novel therapeutic strategies are needed.
Area of Science:
- Neuroscience
- Vascular Biology
- Alzheimer's Disease Research
Background:
- Microangiopathy, characterized by capillary changes and leukocyte blockage, is observed in aged rTg4510 mouse models and Alzheimer's disease (AD).
- Gene expression related to angiogenesis is altered in both rTg4510 mice and human AD patients.
- The direct role of tau protein in causing these vascular changes, either directly or indirectly through neurodegeneration, remains unclear.
Purpose of the Study:
- To investigate the nature of tau-related microangiopathy in human AD and tau mouse models.
- To determine if soluble tau protein directly causes microvascular changes.
- To assess the impact of tau reduction on established vascular pathology.
Main Methods:
- Isolation of capillaries from rTg4510 mouse models and human brain samples.
- Detection of bioactive soluble tau protein associated with vasculature.
- Utilizing a tetracycline-repressible gene expression system in rTg4510 mice to reduce tau levels.
- Measurement of vascular pathology following tau reduction.
Main Results:
- Bioactive soluble tau protein was detected in association with vasculature in both human AD and mouse models.
- Reduction of tau levels in rTg4510 mice did not alter established microvascular complications.
- Key issues like morphological alterations, inflammatory gene expression, and blood-brain barrier compromise persisted despite tau reduction.
Conclusions:
- Soluble bioactive tau accumulates at the blood-brain barrier in human AD and mouse models.
- The morphological and molecular phenotype of microvascular disturbance does not resolve upon reduction of whole-brain soluble tau.
- Targeting tau within the vascular space or employing vascular-directed therapies may be necessary for restoring normal function in neurodegenerative diseases.
