A Vascular Connection to Alzheimer's Disease

Abstract

Alzheimer"s disease (AD) is characterized by a progressive and debilitating dementia in elderly people. The causes of this disease are not known, but major risk factors include old age and a family history of dementia, Down"s syndrome, female gender, low level of education, and head injury. There is no known cure for Alzheimer"s disease. The disease is characterized by abnormal accumulation of amyloid-beta peptide and the protein Tau in the nerve cells and extracellular space of certain regions of the brain. Cerebral amyloid angiopathy is another marker for Alzheimer"s disease. In autopsies, small cerebral arterial blood vessels and capillaries show signs of inflammation, amyloid accumulations, and a focal breach of the blood-brain barrier. This review focuses on the results of recent investigations of vascular responses to infusion of amyloid-beta(1-40), the means of preventing vascular damage, using a live animal (rat) model, and the combination of intravital video recordings of the mesenteric microvascular bed with electron microscopic analyses of the same vascular segments. We propose that the cerebral vascular changes in patients with Alzheimer"s disease probably precede the neuronal damage and dementia.

Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimers Disease Pyramidal Neurons

“…Since it is not clear if the source of accumulated Aβ42 is de novo synthesis in neurons or production elsewhere in the body, some attention should be given to the possibility that it may enter into the brain via a breach in the blood-brain barrier (BBB) [65][66][67][68][69][70][71][72][73]. Intracarotid infusions of Aβ42 contributed to endothelial damage and a significant deterioration of BBB function in the rat [71].…”

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

“…16 Specific attention has recently focused on changes within brain endothelial cells in AD and in response to exposure to Aβ. 16 It has been hypothesized that during the onset of AD the breakdown of the blood-brain barrier results in an neuroinflammatory response leading to increased transport of soluble Aβ across the endothelium, 17,18 the upregulation of inflammatory adhesion molecule expression in response to nuclear factor κB, and subsequent infiltration of inflammatory leukocytes into the brain. 19 This hypothesis has been supported by data showing that Aβ exposure of the basal compartment of endothelial monolayers in culture results in increased monocyte transendothelial migration.…”

A comparison of the anti-inflammatory activities of conjugated estrogens and 17-? estradiol

“…Similar effects were also initiated by other pro-inflammatory agents such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-a) [22]. For reviews of leukocyte-endothelial cell interactions in the inflammatory response, see [21,30].…”

“…We are not aware of other data on leukocyte migration in this or related models, using components present in CEE. As reviewed in detail by us [21], the mechanism of leukocyte/monocyte rolling, margination, adhesion and transmigration in arterioles and venules in response to Ab infusion involves interaction with RAGE receptor (Receptor Vol. 52, 2003 Anti-inflammatory activities 457…”

“…The synthetic selective estrogen receptor modulator (SERM), raloxifene, was devoid of any anti-inflammatory activity [20]. The results of our investigations of vascular responses to infusion of Ab, and means of preventing this damage were recently reviewed by us [21].…”