RanBP9 at the intersection between cofilin and Aβ pathologies: rescue of neurodegenerative changes by RanBP9...

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) production and neurotoxicity.
• Ran Binding Protein 9 (RanBP9) overexpression increases Aβ production, activates cofilin, and causes mitochondrial dysfunction.
• Cofilin translocation to mitochondria and cofilin-actin pathology depend on Slingshot homolog 1 (SSH1) activation and cofilin cysteine oxidation.

Purpose of the Study:

• To investigate the role of endogenous RanBP9 in mediating Aβ-induced neurotoxicity.
• To determine if RanBP9 regulates the SSH1-cofilin pathway in Alzheimer's disease models.
• To assess the therapeutic potential of targeting RanBP9 in vivo.

Main Methods:

• Utilized cell lines, primary neurons, and transgenic mouse models (APP/PS1).
• Assessed cofilin activation, mitochondrial translocation, and cofilin-actin pathology.
• Measured synaptic protein levels, long-term potentiation (LTP), and contextual memory.
• Quantified RanBP9, Aβ, and glial fibrillary acidic protein (GFAP) levels.

Main Results:

• Endogenous RanBP9 positively regulates SSH1 and mediates Aβ-induced cofilin translocation and pathology in vitro and in vivo.
• RanBP9 depletion protected against Aβ-induced growth cone collapse and synaptic protein loss.
• APP/PS1 mice showed increased RanBP9 levels; RanBP9 reduction ameliorated pathology, synaptic damage, and memory deficits.
• RanBP9 reduction enhanced LTP and paired pulse facilitation in APP/PS1 mice.

Conclusions:

• Endogenous RanBP9 is critical for Aβ accumulation and neurotoxicity in Alzheimer's disease.
• RanBP9 mediates Aβ neurotoxic effects via the SSH1-cofilin pathway, impacting synaptic plasticity and mitochondria.
• Targeting RanBP9 represents a promising therapeutic strategy for Alzheimer's disease.