DDR1 regulates CNS collagen IV expression and vascular fibrosis in AD to improve CNS vascular integrity

Abstract

AbstractBackgroundBlood‐brain barrier breakdown, a feature associated with AD pathology and treatments, was examined as a potential therapeutic target in both genetic mouse models of AD and clinical trial data from human patients with AD treated with nilotinib.MethodsDDR1 knockout mice crossed with TgAPP mice were probed for levels of CNS collagen to examine the effects of DDR1 in vivo. CSF samples obtained from AD subjects treated with either nilotinib (n = 12) or placebo (n = 11) for 12 months were analyzed using whole genome RNA sequencing; significantly altered miRNA expression was examined for potential downstream effects regulating neurovascular integrity.ResultsCompared to TgAPP mice, staining of CNS sections for collagen IV in TgAPP/DDR1 knockout mice revealed decreased vascular collagen. CSF obtained from AD subjects treated with nilotinib revealed increased levels of miRNAs regulating collagen production, suggesting decreased vascular fibrosis and neuroinflammation, and improved neurovascular integrity.ConclusionDDR1 inhibition with nilotinib may improve neurovascular integrity in AD by reducing CNS collagen IV, vascular fibrosis, and neuroinflammation. Nilotinib should be considered as an adjunctive therapy to approved treatments ‐ including anti‐amyloid antibodies ‐ for individuals with AD.