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.
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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.
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.
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.
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.
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