Fig. 9.

Schematic representations summarizing key findings of our study. a In this study, we provide evidence that there is overlap of pathology (amyloid plaques, and Aβ₄₂ and p-tau deposition) associated with AD following stroke with key components (BACE1 and NRG1 type III) of a myelin repair pathway in aged stroked wt and stroked hAPP-SL mice. b Working model proposing AD-associated pathology as a chronic sequela of ischemic stroke: chronic inflammation, chronic BBB dysfunction, axonal degeneration, impaired paravascular clearance, and transneuronal degeneration are all chronic sequalae of stroke that may result in stressed myelin homeostasis. BACE1’s role as a protease that cleaves NRG1 type III at its β-site is critical in the formation of myelin sheaths by oligodendrocytes, and is a key regulator of myelination of axons in the central nervous system [10]. BACE1’s cleavage of NRG1 type III initiates γ-secretase cleavage of NRG1 type III at its γ-site. However, in addition to NRG1 type III, BACE1 has high cleavage affinity for the Aβ precursor protein (AβPP). Therefore, the chronic sequelae of stroke may be causing myelin repair mechanisms involving NRG1 type III and BACE1 to be racheted up, resulting in the inadvertent cleavage of AβPP by BACE1 and γ-secretase, and the abnormal generation of amyloidogenic Aβ peptides