miR‐32533 Reduces Cognitive Impairment and Amyloid‐β Overload by Targeting CREB5‐Mediated Signaling Pathways in Alzheimer's Disease

Abstract

Abstract MicroRNAs (miRNAs) are associated with amyloid‐β (Aβ) dysmetabolism, a pivotal factor in the pathogenesis of Alzheimer's disease (AD). This study unveiled a novel miRNA, microRNA‐32533 (miR‐32533), featuring a distinctive base sequence identified through RNA sequencing of the APPswe/PSEN1dE9 (APP/PS1) mouse brain. Its role and underlying mechanisms were subsequently explored. Bioinformatics and confirmatory experiments revealed that miR‐32533 had a novel 23‐base sequence with minimal coding potential, functioning within the Drosha ribonuclease III (Drosha)/Dicer 1, ribonuclease III (Dicer)‐dependent canonical pathway and identifiable via northern blot. miR‐32533 was abundantly brain‐distributed and downregulated in diverse AD‐related models, including APP/PS1 and five familial AD (5×FAD) mouse brains and AD patient plasma. Overexpression or inhibition of miR‐32533 led to improvements or exacerbations in cognitive dysfunction, respectively, by modulating Aβ production, apoptosis, oxidation, and neuroinflammation through targeting cAMP‐responsive element binding protein 5 (CREB5), which interacted with α disintegrin and metalloproteinase 10 (ADAM10), beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1), and presenilin 1 (PS1) promoters, thereby enhancing Aβ production through BACE1 and PS1 upregulation while suppressing non‐amyloidogenic amyloid precursor protein (APP) processing via ADAM10 downregulation. Furthermore, modulation of the miR‐32533/CREB5 axis ameliorated or worsened cognitive impairment by inhibiting or amplifying Aβ overproduction through the BACE1‐involved amyloidogenic and ADAM10‐involved non‐amyloidogenic pathways. Overall, the findings suggest miR‐32533 as a regulator of Aβ metabolism, oxidative stress, and neuroinflammation, establishing the miR‐32533/CREB5 signaling pathways as potential therapeutic targets for combating Aβ accumulation and cognitive deficits in AD.

Keywords

• Alzheimer's disease
• amyloid‐β peptides
• cAMP‐responsive element binding protein 5
• microRNA
• microRNA‐32533