Cerebrovascular Degeneration Is Related to Amyloid-β Protein Deposition in Alzheimer's Diseasea

Authors

  • RAJESH N. KALARIA

    Corresponding author
    1. Departments of Neurology and Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
      b Address for correspondence: Dr. R. N. Kalaria, Department of Neurology (BRB5), Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4938. Phone, 216-368-1113; fax, 216/368-1144.
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  • a

    This work was supported by a grant from the Alzheimer Association (Chicago) and by Grants AG08012, AG08992, and AG10030 from the U.S. Public Health Service.

b Address for correspondence: Dr. R. N. Kalaria, Department of Neurology (BRB5), Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4938. Phone, 216-368-1113; fax, 216/368-1144.

Abstract

ABSTRACT: Current evidence is not inconsistent with the suggestion that cerebrovascular functions decline during normal aging with pronounced effects in both sporadic and familial Alzheimer's disease (AD). The primary causes of these changes remain unknown. It is possible that amyloid β (Aβ) protein is involved in the degeneration of both the larger penetrating vessels as well as the cerebral capillaries that represent the blood-brain barrier (BBB). Aβ-induced endothelial changes could also alter muscular tone, resulting not only in increased expression of vascular amyloid precursor protein (APP) and production of Aβ, but also in oxidative injury. We used immunochemical methods to examine the status of the perfusing cerebral vessels and the microvascular endothelium in relation to deposition of Aβ in AD and non-AD aging control subjects. Double-immunostaining with antibodies to vascular markers revealed marked loss of smooth muscle in larger vessels and absence or attenuation of the endothelium in capillary profiles that still appeared to retain their basement membranes. These vascular changes were predominantly restricted to neocortical regions abundant in Aβ deposits. Quantitative studies showed that the microvascular abnormalities were correlated to Aβ deposition rather than neurofibrillary tangles or neuronal numbers. Our studies suggest that Aβ irrespective of its origin within vascular myocytes or brain parenchyma, is responsible not only for cerebral amyloid angiopathy, but also for the degeneration of the cerebral microvasculature, which may profoundly affect brain perfusion and BBB functions.

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