Targeting Intramural Periarterial Drainage as a therapeutic strategy in Alzheimer’s disease

Accumulation of the β-amyloid (Aβ) protein in cerebral blood vessels is a hallmark of Alzheimer’s disease. Soluble Aβ from the extracellular spaces of the brain is removed along the basement membranes of capillaries and basement membranes surrounding smooth muscle cells of arteries towards the surface of the brain, as intramural periarterial drainage (IPAD). This process depends on the biochemical integrity of the extracellular matrix and the strength of arterial smooth muscle cells. With ageing, possession of Apolipoprotein E4 (APOE4) genotype, hyperlipidemia, maternal high fat, immune complexes, IPAD fails, resulting in the accumulation of proteins in the walls of cerebral arteries as cerebral amyloid angiopathy. The motive force for IPAD is derived from contractions of vascular smooth muscle cells and targeting their function appears to be a promising therapeutic avenue for Alzheimer’s disease. Clusterin (Apolipoprotein J) appears to be a chaperone for Aβ, facilitating IPAD and understanding how it acts upon IPAD is a key direction in therapeutic interventions for Alzheimer’s disease.