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.
Abstract:
Microangiopathy, including proliferation of small diameter capillaries, increasing vessel tortuosity, and increased capillary blockage by leukocytes, was previously observed in the aged rTg4510 mouse model. Similar gene expression changes related to angiogenesis were observed in both rTg4510 and Alzheimer's disease (AD). It is uncertain if tau is directly responsible for these vascular changes by interacting directly with microvessels, and/or if it contributes indirectly via neurodegeneration and concurrent neuronal loss and inflammation. To better understand the nature of tau-related microangiopathy in human AD and in tau mice, we isolated capillaries and observed that bioactive soluble tau protein could be readily detected in association with vasculature. To examine whether this soluble tau is directly responsible for the microangiopathic changes, we made use of the tetracycline-repressible gene expression cassette in the rTg4510 mouse model and measured vascular pathology following tau reduction. These data suggest that reduction of tau is insufficient to alter established microvascular complications including morphological alterations, enhanced expression of inflammatory genes involved in leukocyte adherence, and blood brain barrier compromise. These data imply that 1) soluble bioactive tau surprisingly accumulates at the blood brain barrier in human brain and in mouse models, and 2) the morphological and molecular phenotype of microvascular disturbance does not resolve with reduction of whole brain soluble tau. Additional consideration of vascular-directed therapies and strategies that target tau in the vascular space may be required to restore normal function in neurodegenerative disease.
Insights
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.
