3 August 2007. Mounting epidemiological evidence establishing cardiovascular disease as a risk factor for Alzheimer disease (AD) and suggesting that certain hypertension medications can prevent AD (see ARF related news story) has raised questions about the pathophysiological relationships between the two disorders. Two new studies in mice manipulate and measure the connections between cerebrovascular and amyloid-β (Aβ) pathologies and show that, while vascular deposition of Aβ can impair cardiovascular function, hypertension can also promote Aβ deposition.
Led by Giuseppe Lembo at Neuromed in Pozzilli, Italy, researchers studied mechanistic relationships between hypertension, one of the risk factors for AD, and brain deposition of Aβ. Writing in the July 27 Neurobiology of Aging online, Lembo and his coauthors describe their study as the first demonstration “that chronic hypertension determines an impairment of the blood-brain barrier permeability with Aβ deposition in brain.”
First author Maria Teresa Gentile and colleagues used surgical (transverse aortic constriction, TAC) and pharmacological (chronic infusions of angiotensin II via subcutaneous osmotic minipumps) protocols to increase blood pressure. Both yielded similar increases in Aβ deposition: compared to noromotensive mice, hypertensive mice showed increased blood-brain permeability and cerebral deposition of the peptide in the cortex and hippocampus. Further, Western blots indicated a time-dependent increase in Aβ-like fragments such that greater staining coincided with longer delays between TAC and sacrifice.
As the researchers wrote, the increased Aβ staining and blood-brain barrier permeability “suggested a bloodstream origin of the brain amyloid deposits rather than a neuronal source.” To clarify the source, the researchers administered an IgG against Aβ to suppress Aβ passage from the bloodstream. “We observed that hypertensive mice treated with passive immunotherapy showed a markedly reduced Aβ immunopositivity in both cortex and hippocampus as compared to hypertensive mice treated with vehicle alone,” wrote Gentile and colleagues.
The second study, by Cenk Ayata’s research team at Harvard Medical School, takes an alternative view of the relationship between cardiovascular and Alzheimer diseases by studying how Aβ deposition alters blood vessels. The authors note previous work linking soluble Aβ and impaired cerebrovascular function. “This association was apparent prior to vascular Aβ deposition, raising the possibility that elevated Aβ levels in AD brain may adversely impact progression of the disease via hemodynamic mechanisms,” wrote the Harvard researchers in the July 16 Brain.
To elucidate the cerebrovascular effects of soluble versus Aβ deposits, first author Hwa Kyoung Shin and colleagues used the Tg2576 model of AD, which exhibits extensive cerebral amyloid angiopathy (CAA). In this transgenic model, brain Aβ levels rapidly increase at 7 months of age, and at 9 months of age vascular Aβ deposition is apparent.
The authors measured hemodynamics, or blood flow, using laser speckle flowmetry through the intact skull. They found that 8-month-old CAA transgenic mice with increased soluble Aβ but no vascular Aβ deposits had the same blood flow responses to stimuli that affect vasomotor responses as did 3-month-old wild-type mice. However, the researchers found that age altered cerebral blood flow and Aβ. Nineteen-month-old mice with CAA showed severe Aβ deposition and impairments to vasomotor-altering stimuli.
The data indicate that Aβ deposition impairs blood flow, but only when the AD-related peptide is deposited in the vasculature. That is, Shin and colleagues conclude that free-floating, soluble Aβ does not impair blood flow, a finding that resounds with many reports linking Aβ deposition to vascular dysfunction.—Molly McElroy.
Molly McElroy is a freelance writer based in Melbourne, Florida.
Gentile MT, Poulet R, Pardo AD, Cifelli G, Maffei A, Vecchione C, Passarelli F, Landolfi A, Carullo P, Lembo G. b-amyoid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiology of Aging. 2007, July 27. Abstract
Shin HK, Jones PB, Garcia-Alloza M, Borrelli L, Greenberg SM, Bacskai BJ, Frosch MP, Hyman BT, Moskowitz MA, Ayata C. Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain. 2007, July 16. Abstract