Hypertension Begets Aβ, Begets Cardiovascular Damage

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.

 

Comments

  1. Shin and colleagues’ findings that advanced aging in the amyloid angiopathic Tg2576 mouse model reduces their ability to vasodilate or vasoconstrict pial vasculature following various vasomotor challenges adds another bit of mystery to the topic of age-related cerebral blood flow regulation. Although the focus of their study was to challenge the notion that elevated soluble Aβ levels are insufficient to cause vasomotor dysfunction, other relevant questions arise. For example, it is reported that memory impairment in the Tg2576 mouse model begins at 6 months (1) at a time when parenchymal or vessel amyloid deposits are not yet seen, but soluble Aβ levels are starting to rise. What then drives the earlier memory impairment in this model? Is it evolving Aβ deposits in the parenchyma or in brain vessels or "something" else? Since cerebral hypoperfusion is consistently one of the earliest pathological events found in sporadic Alzheimer disease (2), one needs to look at Shin and colleagues’ data from the possible perspective that CBF reduction (from whatever cause) in their 8-month-old Tg2576 mutant progressively drives Aβ overproduction in the parenchyma and vessels, and it is the latter abnormality that destroys the vessels’ structural integrity to regulate and maintain a functional cerebral hemodynamic state.

    References:

    Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1858-67. PubMed.

    Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol. 2005 Jun;57(6):789-94. PubMed.

    View all comments by Jack de la Torre

  2. Shin and colleagues have provided very interesting evidence of the physiological dysfunction resulting from CAA in a transgenic mouse model. In humans CAA is usually accompanied by other features of Alzheimer pathology such as plaques and tangles. Accumulation of amyloid in the vessel wall renders the wall more rigid and damages the smooth muscle cells. It has long been postulated that the consequence of this would be impairment of the exquisitely precise matching of perfusion of the cerebral cortex to local neuronal metabolic demand which occurs on a microscopic scale. The application of very elegant new technology of laser speckle flowmetry has allowed non-invasive mapping of flow in the network of cortical vessels in response to several stimuli including hypercapnia, whisker stimulation, cortical spreading depression, and anaesthetics. These studies show that there is an age-related impairment of vascular reactivity which is further worsened by the presence of Aβ in the walls of the blood vessels. Both vasoconstriction and vasodilatation are impaired.

    This study is very valuable in focusing thoughts on the extent to which impaired autoregulation of cerebral blood flow might contribute to dementia in patients who have both age-related vascular stiffening and CAA. Of course, ApoE ε4, the major genetic risk factor for sporadic AD, correlates strongly with the presence of CAA and also other age-related vascular abnormalities such as atherosclerosis and arteriosclerosis. Blood vessel dysfunction due to vascular pathology, as shown in this study, could therefore conceivably be an important mechanism mediating the risk of ApoE ε4 for dementia.

    View all comments by James Nicoll

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References

News Citations

  1. No Pressure, But Could Hypertension Medication Prevent AD?

Further Reading

Primary Papers

  1. 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 Sep;130(Pt 9):2310-9. PubMed.
  2. Gentile MT, Poulet R, Di Pardo A, Cifelli G, Maffei A, Vecchione C, Passarelli F, Landolfi A, Carullo P, Lembo G. Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009 Feb;30(2):222-8. PubMed.

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