Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Chronic stress, elevated glucocorticoids (GCs), and aging are risk factors for Alzheimer's disease (AD).
• AD pathogenesis involves amyloid-beta (Aβ) overproduction and hyperphosphorylated Tau accumulation.
• Rab35, a small GTPase, is linked to Tau degradation but its role in Aβ production is unclear.

Purpose of the Study:

• To investigate the role of Rab35 in Alzheimer's disease (AD) pathogenesis, specifically its involvement in amyloid-beta (Aβ) production.
• To determine if stress, glucocorticoids (GCs), and aging affect Rab35 levels and its regulation of Aβ production.

Main Methods:

• Quantification of hippocampal Rab35 levels in response to stress, GCs, and aging.
• Analysis of Rab35's regulation of amyloid precursor protein (APP) and β-secretase (BACE1) trafficking using cellular and molecular biology techniques.
• Investigation of Rab35 effector proteins (OCRL and ACAP2) in coordinating APP and BACE1 trafficking.
• Assessment of Rab35 overexpression effects on GC-induced amyloidogenic trafficking.

Main Results:

• Hippocampal Rab35 levels decrease with stress, GCs, and aging.
• Rab35 negatively regulates Aβ production by controlling the intracellular trafficking of APP and BACE1.
• Rab35 mediates distinct trafficking pathways for BACE1 (via OCRL) and APP (via ACAP2).
• Overexpression of Rab35 prevents stress hormone-induced amyloidogenic trafficking of APP and BACE1.

Conclusions:

• Rab35 is a critical regulator of APP processing and Aβ production.
• Downregulation of Rab35 contributes to amyloidogenesis in stress-related and age-related Alzheimer's disease.
• Targeting Rab35 may offer a therapeutic strategy for Alzheimer's disease.