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Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T. Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3587-92. PubMed.
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University of Texas at Austin
I have been a longtime admirer of Thomas Krucker’s vascular corrosion casting studies in mice, which resemble a 3-D micro-CT scan but are much more detailed and analyzable. They are especially useful when combined with magnetic resonance angiography imaging. In the present study, Krucker and his colleagues reveal changes observed in the cerebrovascular architecture of APP23 tg mice who were followed in an age-dependent time period lasting 25 months. During that time, parenchymal amyloid plaques appeared in the transgenic group, but only following significant microvascular changes. The slowly evolving microvascular pathology prior to plaque formation that the authors observed in the APP23 mice indicated to them that the disrupted microvessels ostensibly contribute to the early memory/learning deficits seen in this transgenic mouse model. The authors further conclude that early damage in the tg microvessels may worsen progressively over time, and could reflect the actual pathogenesis of AD, a point we have argued for many years (1).
These experimental observations confirm, and possibly explain, an increasing number of neuroimaging studies in humans that reveals preclinical reduced regional cerebral blood flow in people who later convert to AD (2). One caveat to be noted is that there is always a potential fallacy in assuming that gene mutation of APP or presenilins in mice or humans which produce excess Aβ also explain the pathological cascade seen in sporadic AD. This is a sophistic assertion that has gotten us into trouble for the last 20 years in our search for a cure to this dementia, and disregards the critical role of environmental risk factors to AD which are often present decades prior to plaque or tangle formation (3). However, having said that, there is evidence that brain hypoperfusion may trigger the expression of AD symptoms in people who carry the PS1 mutation (4), while hypoxia is reported to upregulate BACE1 (5).
References:
de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer's disease?. Neurol Res. 1993 Jun;15(3):146-53. PubMed.
Caroli A, Testa C, Geroldi C, Nobili F, Barnden LR, Guerra UP, Bonetti M, Frisoni GB. Cerebral perfusion correlates of conversion to Alzheimer's disease in amnestic mild cognitive impairment. J Neurol. 2007 Dec;254(12):1698-707. PubMed.
Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging. 2000 Mar-Apr;21(2):153-60. PubMed.
Johnson KA, Lopera F, Jones K, Becker A, Sperling R, Hilson J, Londono J, Siegert I, Arcos M, Moreno S, Madrigal L, Ossa J, Pineda N, Ardila A, Roselli M, Albert MS, Kosik KS, Rios A. Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology. 2001 Jun 12;56(11):1545-51. PubMed.
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18727-32. PubMed.
Weill College Medicine, New York
The authors investigated the vascular alterations occurring in a mouse model of Alzheimer disease (AD) using corrosion casts and scanning electron microscopy. They report that APP23 mice exhibit structural alterations in cerebral microvessels before full-blown amyloid plaque deposition occurs. These alterations include formation of perivascular microdeposits, distortion, and remodeling of cerebral microvessels. As the accumulation of amyloid progresses, there are areas of loss of blood vessels that correspond to amyloid deposits and are surrounded by a halo of increased vascularization.
These observations provide a striking demonstration of the severe microvascular disruption in APP23 mice that develop well before the onset of cognitive decline. These highly restricted microvascular alterations fit well with the disruption in cerebrovascular regulation reported in APP mice. APP mice exhibit severe reduction in functional hyperemia, a vital homeostatic mechanism that matches local energy requirements with blood flow, and in the ability of cerebral microvessels to vasodilate in response to endothelial signals. The exquisite vascular localization of the early deposition fits well with these functional alterations.
However, recent studies demonstrate that the functional alterations in APP mice can be quickly counteracted by suppressing oxidative stress (Park et al., 2008) 2008). Therefore, the perivascular microdeposits described by Krucker et al. are unlikely to produce irreversible vascular damage. They may contribute to the dysfunction by, for example, being a source of vascular oxidative stress.
The recent Nature paper from the group of Brad Hyman (Meyer-Luehmann et al., 2008) did not identify the vessel wall as the first site of amyloid deposition, although a perivascular localization was found. The differences with the study of Krucker might be in the techniques used to detect amyloid deposits, i.e., corrosion casts vs. methoxy-XO4, and, most importantly, the transgenic animals used. Rapidly evolving imaging approaches in humans may provide data in AD and verify these provocative findings in animal models.
Overall, this is a nice study that provides a novel perspective of the microvascular disruption that occurs in a model of APP overexpression and Aβ accumulation.
References:
Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1347-52. PubMed.
Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 2008 Feb 7;451(7179):720-4. PubMed.
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