Altered ubiquitin signaling induces Alzheimer's disease-like hallmarks in a three-dimensional human neural cell culture model.

ABSTRACT: Alzheimer's disease (AD) is characterized by toxic protein accumulation in the brain. Ubiquitination is essential for protein clearance in cells, making altered ubiquitin signaling crucial in AD development. A defective variant, ubiquitin B + 1 (UBB⁺¹), created by a non-hereditary RNA frameshift mutation, is found in all AD patient brains post-mortem. We now detect UBB⁺¹ in human brains during early AD stages. Our study employs a 3D neural culture platform derived from human neural progenitors, demonstrating that UBB⁺¹ alone induces extracellular amyloid-β (Aβ) deposits and insoluble hyperphosphorylated tau aggregates. UBB⁺¹ competes with ubiquitin for binding to the deubiquitinating enzyme UCHL1, leading to elevated levels of amyloid precursor p

SUBMITTER: Maniv I 

PROVIDER: S-EPMC10516951 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature