Navβ2 Intracellular Fragments Contribute to Aβ1-42-Induced Cognitive Impairment and Synaptic Deficit Through Transcriptional Suppression of BDNF

A pathological hallmark of Alzheimer's disease (AD) is the region-specific accumulation of the amyloid-beta protein (A beta), which triggers aberrant neuronal excitability, synaptic impairment, and progressive cognitive decline. Previous works have demonstrated that A beta pathology induced aberrant elevation in the levels and excessive enzymatic hydrolysis of voltage-gated sodium channel type 2 beta subunit (Nav beta 2) in the brain of AD models, accompanied by alteration in excitability of hippocampal neurons, synaptic deficits, and subsequently, cognitive dysfunction. However, the mechanism is unclear. In this research, by employing cell models treated with toxic A beta 1-42 and AD mice, the possible effects and potential mechanisms induced by Nav beta 2. The results reveal that A beta 1-42 induces remarkable increases in Nav beta 2 intracellular domain (Nav beta 2-ICD) and decreases in both BDNF exons and protein levels, as well as phosphorylated tropomyosin-related kinase B (pTrkB) expression in cells and mice, coupled with cognitive impairments, synaptic deficits, and aberrant neuronal excitability. Administration with exogenous Nav beta 2-ICD further enhances these effects induced by A beta 1-42, while interfering the generation of Nav beta 2-ICD and/or complementing BDNF neutralize the Nav beta 2-ICD-conducted effects. Luciferase reporter assay verifies that Nav beta 2-ICD regulates BDNF transcription and expression by targeting its promoter. Collectively, our findings partially elucidate that abnormal enzymatic hydrolysis of Nav beta 2 induced by A beta 1-42-associated AD pathology leads to intracellular Nav beta 2-ICD overload, which may responsible to abnormal neuronal excitability, synaptic deficit, and cognition dysfunction, through its transcriptional suppression on BDNF. Therefore, this work supplies novel evidences that Nav beta 2 plays crucial roles in the occurrence and progression of cognitive impairment of AD by transcriptional regulatory activity of its cleaved ICD.