This invention relates to the field of
organoid disease models, and discloses a method for constructing a
human brain organoid model of early-onset Alzheimer's
disease (AD) and its applications. This invention introduces [a specific technology] into human
embryonic stem cell lines through single-base editing and lead editing techniques. PSEN1 ΔE9、 PSEN1 M146V and APP Human
embryonic stem cell lines carrying four familial pathogenic
gene mutations (K670N and M671L) were constructed and induced to differentiate into Alzheimer's
disease (AD) brain organoids. The AD brain
organoid model established by this invention exhibited tau
phosphorylation pathological phenotypes as early as 20 days and Aβ-related phenotypes as early as 40 days, with increased total Aβ, decreased Aβ42 / Aβ40 ratio, and simultaneous aggravation of Aβ-
Tau pathology. This represents a complex neurodegenerative
pathological model where multiple mutations synergistically regulate Aβ production and tau
phosphorylation, which is highly valuable for understanding and studying early-onset familial AD. This invention provides a
human brain organoid model for
in vitro AD studies and offers a tool for studying the
pathological mechanisms of AD and screening drugs.