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

Abstract

AbstractBackgroundAlzheimer’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.MethodTo investigate this, we generated a transgenic mouse line carrying the membralin gene, which expression was driven by a Prion promoter, and crossed this mouse line with 5XFAD mice. We performed behavioral studies using the Barnes Maze, Morris Water Maze, and Fear Conditioning tests on the 6‐month‐old animals. Biochemical and pathological analyses were used to determine the load of beta‐amyloid accumulation and neuroinflammation phenotype.ResultElevation of membralin improved spatial learning and memory in 5xFAD mice. Abeta 42 and Abeta 40 levels significantly reversely correlated with the membralin protein level. The abeta plaques appeared to be compact, and there were more microglia associated with the abeta plaques in the membralin transgenic animals crossed with the 5xFAD animals.ConclusionOverall, this suggests that elevation of membralin improves beta‐amyloid‐associated cognitive decline. And this could be partially from the effects of membralin in regulating neuroinflammation. Modulation of glial ER homeostasis could be a promising target to regulate neuroinflammation for AD therapy.