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Impaired clearance of amyloid-beta causes vascular damage in Alzheimer’s disease


New research suggests that accumulation of amyloid-â 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-â (Aâ) deposition is a hallmark of Alzheimer’s disease and other cerebral amyloid angiopathies. However, exactly how Aâ accumulates and causes damage is not fully understood.

In the first article, "Cerebral microvascular Aâ deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant AâPP," Miao et al. describe early-onset Aâ deposition in Tg-SwDI mice. These mice express Aâ protein with mutations that are found in human early-onset cerebral amyloid angiopathy, causing specific accumulation of Aâ in cerebral blood vessels.

The Aâ peptides accumulated because they could not adequately cross the blood-brain barrier to be cleared from the brain. Over time, Aâ 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 Aâ accumulation.

The authors conclude that early-onset Aâ 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 Aâ, and were used to investigate the possible association of blood vessels with Aâ 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 Aâ 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 Aâ 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 Aâ 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 Aâ generated by neurons accumulates in blood vessels following attempted clearance of excess Aâ peptides. Thus, study of novel therapies that reduce the blood vessel-associated deposition of Aâ may prove beneficial to patients with Alzheimer’s disease.

Audra Cox | EurekAlert!
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