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Mechanisms of cerebrovascular amyloid deposition. Lessons from mouse models
P Burgermeister1, M E Calhoun, D T Winkler
1Department of Neuropathology, University of Basel, Switzerland.
Abstract:
Cerebrovascular deposition of amyloid is a frequent observation in Alzheimer's disease patients. It can also be detected sporadically in normal aged individuals and is further found in familial diseases linked to specific gene mutations. The source and mechanism of this pathology are still unknown. It has been suggested that amyloidogenic proteins are derived from blood, the vessel wall itself, or from the central nervous system. In this article evidence is reviewed for and against each of these hypotheses, including new data obtained from transgenic mouse models. In APP23 transgenic mice that develop cerebral amyloid angiopathy (CAA) in addition to amyloid plaques, the transport and drainage of neuronally produced amyloid-beta (A beta) seem to be responsible for CAA rather than vascular A beta production or blood uptake. Although a number of mechanisms may contribute to CAA in humans, these results suggest that a neuronal source of A beta is sufficient to induce vascular amyloid deposition. The possibility to cross genetically defined mouse models of CAA with other mutant mice now has the potential to identify molecular mechanisms of CAA.
Insights
Cerebrovascular amyloid deposition, common in Alzheimer's disease, may stem from neurons. Studies in APP23 mice suggest neuronal amyloid-beta (Aβ) transport causes this vascular pathology.
Area of Science:
- Neurology
- Neuroscience
- Pathology
Background:
- Cerebrovascular amyloid deposition is prevalent in Alzheimer's disease (AD) and aging.
- Its origin remains unclear, with hypotheses including blood, vessel wall, or central nervous system sources.
Purpose of the Study:
- To investigate the source and mechanism of cerebrovascular amyloid deposition.
- To evaluate the role of neuronally derived amyloid-beta in cerebral amyloid angiopathy (CAA).
Main Methods:
- Review of existing evidence on amyloidogenic protein sources.
- Analysis of data from APP23 transgenic mouse models exhibiting amyloid plaques and CAA.
Main Results:
- In APP23 mice, CAA development is linked to the transport and drainage of neuronally produced amyloid-beta (Aβ).
- Neuronal Aβ production appears sufficient to induce vascular amyloid deposition, independent of vascular Aβ production or blood uptake.
Conclusions:
- Neuronal origin of Aβ is a key factor in cerebrovascular amyloid deposition.
- Future research using genetically modified mouse models can elucidate molecular mechanisms of CAA.