New research suggests that accumulation of amyloid-β peptides in cerebral blood vessels, as opposed to the brain itself, may be a more important pathological mediator of Alzheimer's disease. Two independent yet related articles describe such findings in the August issue of The American Journal of Pathology. Both articles are highlighted on the Journal's cover.
Alzheimer's disease, the most common form of progressive dementia, affects an estimated 4.5 million Americans according to the Alzheimer's Association. Amyloid-β (Aβ) deposition is a hallmark of Alzheimer's disease and other cerebral amyloid angiopathies. However, exactly how Aβ accumulates and causes damage is not fully understood.
In the first article, "Cerebral microvascular Aβ deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant AβPP," Miao et al. describe early-onset Aβ deposition in Tg-SwDI mice. These mice express Aβ protein with mutations that are found in human early-onset cerebral amyloid angiopathy, causing specific accumulation of Aβ in cerebral blood vessels.
The Aβ peptides accumulated because they could not adequately cross the blood-brain barrier to be cleared from the brain. Over time, Aβ accumulation increased in the cerebral microvessels of the thalamus and subiculum of the brain. This resulted in degeneration of blood vessels as evidenced by reduced vessel density and increased apoptosis. Neuroinflammation also occurred as large numbers of microglia, along with inflammatory cytokines, were found at sites of Aβ accumulation.
The authors conclude that early-onset Aβ accumulation occurs predominantly in the cerebral microvasculature and appears largely responsible for the neuroinflammation in these mice. They also demonstrate the utility of Tg-SwDI mice in studying cerebral amyloid angiopathies, such as Alzheimer's disease.
The second article, by Kumar-Singh et al., "Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls," utilizes two different transgenic mice: Tg2576 and PSAPP. Both models produce dense-core plaques, highly concentrated deposits of Aβ, and were used to investigate the possible association of blood vessels with Aβ deposits.
In these mice, dense-core plaques associated with cerebral vessels with high specificity. There was also evidence of vessel damage and blood-brain barrier damage, resulting in release of Aβ through the vessel walls and accumulation of plaques next to the vessels. These data confirm previous observations in humans that senile plaques associate with blood vessels, especially in the vasculotropic Flemish type of Alzheimer's disease.
The authors propose a model of dense-core plaque formation that is dependent on cerebral vessels. As Aβ is cleared from the brain, it exerts a cytotoxic effect on the endothelial cells of the vascular wall (a process that may be exacerbated if clearance is impaired). This leads to loss of vessel integrity and accumulation of Aβ in the area surrounding the compromised vessel wall. Eventually, the damage is so great that the blood vessel deteriorates beyond functional use and new vessels form to pick up the slack. The result is a multicentric dense-core plaque that associates with multiple vessels.
These studies describe several animal models for further examining the pathogenesis and treatment of Alzheimer's disease and related cerebral amyloid angiopathies. And both studies confirm that Aβ generated by neurons accumulates in blood vessels following attempted clearance of excess Aβ peptides. Thus, study of novel therapies that reduce the blood vessel-associated deposition of Aβ may prove beneficial to patients with Alzheimer's disease.
*Miao J, Xu F, Davis J, Otte-Höller I, Verbeek MM, Van Nostrand WE: Cerebral microvascular Aβ deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant AβPP. Am J Pathol 2005, 167: 505-515
†Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C: Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. Am J Pathol 2005, 167: 527-543
*Work was performed at Stony Brook University, New York. †Work was performed at the Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
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