Therapeutic targets for improving intramural periarterial drainage (IPAD) in the prevention and treatment of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease

R. Carare 2017, R.O.Carare@soton.ac.uk

Intramural periarterial drainage (IPAD) of fluid and soluble peptides from the brain parenchyma occurs along the basement membranes of cerebral capillaries and arteries, against the direction of blood flow and towards the leptomeningeal arteries (1). Failure of IPAD with increasing age is associated with the failure of elimination of Aβ from the brain, CAA and Alzheimer’s disease. Genetic mutations involving amyloidogenic peptides, such as Aβ and Cystatin, also result in CAA.

Experimentally, IPAD is impaired in [a] aged mice, [b] in the presence of CAA, [c] in mice with human apolipoprotein E4 genotype, [d] in mice with hyperlipidemia associated with maternal high fat diet during gestation, and [e] in mice associated with the formation of immune complexes in IPAD pathways (2)(3)(4)(5)(6)(7). Changes in the extracellular matrix within artery walls are reflected in the structural, morphological and biochemical modifications of the vascular basement membranes and are associated with CAA (8)(9).

Although the driving force for IPAD was originally thought to be derived from the pulsations from the heart, the biophysical properties of the pulse wave are not adequate for efficient IPAD (10). Instead, recent mathematical modelling demonstrates that the contraction of smooth muscle cells in the walls of cerebral arterioles, and possibly of pericytes in the walls of capillaries, would generate a process termed vasomotion of the appropriate amplitude and wavelength to provide the motive force for IPAD (Aldea R, PhD thesis submitted Nov 2017, manuscript in preparation).

The observations from human CAA and from experimental studies of those factors that impair IPAD suggest two major therapeutic strategies may prevent or ameliorate CAA and Alzheimer’s disease: [a] Maintaining the tone of artery walls: [b] Preventing and retarding the onset of arteriosclerosis. Age changes and arteriosclerosis weaken contraction of intramural cells, particularly smooth muscle cells in the tunica media of arteries, and also induced changes in the extracellular matrix, particularly the basement membranes of smooth muscle cells that form the IPAD pathway. Preventing age changes in the walls of arteries, stimulating smooth muscle cell contraction and improving IPAD are promising strategies for the prevention of CAA and Alzheimer’s disease.

Strategies for improving IPAD

Agents that improve contractility of vascular smooth muscle cells: Phosphodiesterase III is the major cAMP-hydrolyzing PDE uniquely expressed in vascular smooth muscle cells; PDE IIIA isoforms are also involved in cardiovascular function by regulating vascular smooth muscle growth and phenotypic changes. Cilostazol is a selective inhibitor of PDE III that increases cAMP in vascular cells and has multiple effects on the vasculature such as vasodilatation, anti-oxidation, anti-inflammation, regulation of smooth muscle cells, increase in cerebral haemodynamics and arterial elasticity with maintenance of microvascular integrity, as reviewed in (11). Cognition is significantly improved in experimental models and in humans receiving Cilostazol (12)(13)(14)(15). Administration of Cilostazol significantly improves IPAD and the brains of mice treated with Cilostazol show effects upon extracellular matrix, with upregulation of the anti-fibrillogenic glycoproteins (16)(17).

Using chaperones for efficient transport along the IPAD pathways: Clusterin (Apolipoprotein J) is a multifunctional protein that reduces the aggregation and toxicity of Aβ and appears to be beneficial in atherosclerosis (18)(19). We recently demonstrated that in APP/PS1 mouse models of Alzheimer’s disease, crossed with clusterin knockout mice, result in disappearance of Aβ plaques but an increase in severity of CAA. These findings suggest that clusterin is required for efficient chaperoning of solubilized proteins from plaques along IPAD (20). Administration of clusterin as a preventative therapy when the integrity and function of smooth muscle cells and basement membranes are not compromised may yield positive results for the prevention or delay in onset of symptoms of CAA and Alzheimer’s disease. Taxifolin is flavonoid that appears to maintain amyloid in its soluble forms more amenable for clearance (21). We are investigating whether Taxifolin facilitates IPAD.

Agents acting upon the innervation of smooth muscle cells: Experimental work is ongoing in this area. Results suggest that agents such as Prazosin, an alpha(1)-adrenoceptor antagonist, acting upon cholinergic or adrenergic innervation of cerebral arteries result in improvements of IPAD and in reduction of CAA in transgenic mouse models of Alzheimer’s disease (22).

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