New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy

Abstract

Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD.

Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy

“…Taxifolin maintained cerebrovascular integrity in Tg-SwDI mice, which might facilitate vascular-mediated removal of amyloid-β from the brain [58]. Furthermore, disentangled amyloid-β may have been cleared more efficiently through transcytosis across BBB as well as the perivascular lymphatic drainage (PVD) system [3].…”

“…Swedish/Dutch/Iowa mutant amyloid-β impaired its cerebrovascular-mediated clearance system resulting in robust amyloid-β accumulation within cerebral vessels [13]. Since decreased elimination, rather than increased production, of amyloid-β is likely to be a major cause of sporadic CAA, as well as Alzheimer’s disease [44], this model is useful for investigating mechanisms and therapeutic approaches in CAA [57, 58]. …”

APP/Aβ structural diversity and Alzheimer's disease pathogenesis

“…There is also considerable uncertainty over where Aβ accumulation first occurs in the brain and whether the deposited molecules are generated within the brain exclusively or augmented by peripheral pools. Under normal circumstances Aβ is proteolytically degraded in brain or cleared by the liver and kidneys [204–206], but very little is known about the catabolism of the PTM Aβ peptides. Adding to these complexities, a variety of homogeneous or heterogeneous aggregated Aβ species could be stochastically generated in brain tissue.…”

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

“…These revelations further hint at the possible implications of TREM2 and sTREM2 in other cognitive dysfunction-causing diseases such as cerebral amyloid angiopathy [37]. Accordingly, future findings are expected to give prominence to the significance of TREM2 and sTREM2 as key targets in prediction, prevention and/or improvement of cognitive dysfunction.…”