Elevation of membralin can improve the cognitive decline in 5xFAD mice

Alzheimer’s Disease (AD) is the most prominent neurodegenerative dementia in the aging human population, with pathological hallmarks that include deposition of extracellular β‐amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Aging is one of the largest risk factors for developing AD. Disturbed protein homeostasis is associated with the aging process. However, the cell‐type‐specific contribution of disturbed protein homeostasis to the aging process and AD progression is unclear. Our previous works identified a novel Endoplasmic‐Reticulum‐Associated Degradation (ERAD) component, membralin/TMEM259, which can mediate the turnover of nicastrin protein, consequently affect gamma‐secretase complex formation and activity. Knockdown membralin in an AD mouse model (TgCRND8) exaggerated beta‐amyloid‐associated neuronal damage. Moreover, selective deletion of membralin in astrocytes decreased excitatory amino acid transporter 2 (EAAT2) expression and induced neuroinflammation. Therefore, we hypothesized that elevation of membralin would improve beta‐amyloid‐associated cognitive decline and alleviate neuroinflammation.