Proinflammatory and Vasoactive Effects of Aβ in the Cerebrovasculature

Abstract

Abeta peptides are thought to be critical molecules in the pathophysiology of Alzheimer's disease (AD) and are the major protein constituents of senile plaques. In most AD cases, Abeta peptides also form some deposits in the cerebrovasculature, leading to cerebral amyloid angiopathy and hemorrhagic stroke. Regional cerebral hypoperfusion is one of the earlier clinical manifestations in both the sporadic and familial forms of AD. In addition, a variety of vascular risk factors of different etiologies (for instance, diabetes, hypertension, high cholesterol level, atherosclerosis, and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of Abeta on constrictor responses elicited by endothelin-1 in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized Abeta potentiates endothelin-1-induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoconstriction elicited by Abeta in these large human cerebral arteries appears to be completely antagonized by NS-398, a selective cyclooxygenase-2 inhibitor, or by SB202190, a specific p38 mitogen-activated protein kinase inhibitor, suggesting that Abeta vasoactivity is mediated via the stimulation of a proinflammatory pathway. In addition, a similar proinflammatory response appears to be mediated by Abeta in isolated human brain microvessels, resulting in an increased production of prostaglandin E(2) and F(2alpha). Using a scanner laser Doppler imager, we show a progressive decline with aging in cortical perfusion level in transgenic APPsw mice (line 2576) compared with age-matched control littermates. The relation between the acute proinflammatory and vasoactive properties of Abeta and the chronic progressive hypoperfusion seen in AD (and transgenic models thereof) is yet to be elucidated.

Investigation of one-lung ventilation postoperative cognitive dysfunction and regional cerebral oxygen saturation relations

“…Each patient was given two sets of similar questions before and after surgery, and 10 cases of normal cases formed the control group. The Z scoring method was used to exclude the effect of any learning effects caused by the short-term repeat of two tests (Grilli et al, 1996;Kienlen-Campard et al, 2000;Townsend et al, 2002). The experimental results showed that the two groups of patients with or without POCD had no obvious differences in cognitive functions before the operation.…”

Short Amyloid-β (Aβ) Immunogens Reduce Cerebral Aβ Load and Learning Deficits in an Alzheimer's Disease Mouse Model in the Absence of an Aβ-Specific Cellular Immune Response

“…Recently, Deane et al (2005) showed that anti-A␤ IgG increases A␤ clearance from the brain through effects on A␤ transport across the blood-brain barrier mediated by neonatal FcR (FcRn) or low-density lipoprotein receptor-related protein-dependent mechanisms (Deane et al, 2005). These mechanisms may be combined with other effects such as masking the proinflammatory and vasoactive effect of A␤ in the cerebrovasculature (Townsend et al, 2002) by antibodies, particularly in light of recent reports regarding brain-volume changes after A␤ immunotherapy . We observed increased levels of TBS-soluble A␤ after immunization with R-2ϫA␤1-15, suggesting that perhaps the antibodies caused disaggregation of A␤, presumably in the CNS, or alternatively, prevented the aggregation of A␤ over the immunization period.…”

Familial Alzheimer disease in Latinos

“…One potential explanation is that stroke in persons with APOE-ε4 may promote the pathologic process of AD. Alternatively, the presence of APOE-ε4 may modify the brain's response to vascular injury (33,34), increasing the degree of cognitive dysfunction resultant from a given stroke in a patient with incipient AD. Although little is known about the possible role of APOE in the molecular events following stroke in the setting of AD, the relationship between vascular injury, APOE and AD on a molecular level is deserving of further study.…”