Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply

Abstract

The integrity of the vasculature and the maintenance of the blood supply to the brain are crucial for the survival of higher vertebrates. However, peripheral mechanisms of sealing the vasculature that rely on the clotting of blood and platelet aggregation around the site of a 'leak' would lead to decreased cerebral perfusion and compromise the viability of terminally differentiated and irreplaceable neurons. Therefore, in higher organisms it is likely that a sealant/anti-coagulant system that maintains vascular supply has evolved as a necessity to life. We propose that one such system involves the amyloid-beta precursor protein (AbetaPP) and its cleavage product Abeta since (1) both AbetaPP/Abeta are known to deposit in the media of the cerebrovasculature wall following localized injury, (2) Abeta is generated from AbetaPP, a known acute phase reactant, (3) Abeta's physiochemical properties allow it to span between the extracellular matrix and the (endothelial) cell membrane and under inflammatory conditions aggregate to form an intracranial 'scab', thereby maintaining structural integrity of the blood brain barrier, (4) AbetaPP/Abeta together act as an anti-coagulant, (5) Abeta promotes vascular/neuronal remodeling, and (6) Abeta deposits resolve after injury. These properties are consistent with the acute phase generation and rapid cortical deposition of AbetaPP/Abeta following injury (either sustained by trauma or stresses associated with aging) that would be an important compensatory response aimed at limiting the loss of terminally differentiated neurons. Such a system would allow the maintenance of blood supply to the brain by sealing vascular lesions, preventing hemorrhagic stroke while at the same time inhibiting the coagulation cascade from blocking capillaries. Obviously, strategies to remove Abeta would have serious consequences for the integrity of the blood-brain barrier. Indeed, recent in vivo evidence demonstrates that the removal of deposited Abeta from the vasculature leads to increased cerebral microhemorrhage and strongly support the above mentioned functions of AbetaPP/Abeta. These insights also explain the root cause of the encephalitis and meningitis suffered by individuals in immunotherapy trials as being directly associated with the removal of Abeta from the vasculature, i.e. immunological responses to Abeta vaccination do not discriminate between physiologically purposive deposits of Abeta (vascular deposits) and pathological deposits of Abeta (senile plaques).