Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids.

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer's disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1^ΔE9/WT, PSEN1^M146V/WT, or APP^swe/WT. Our CO model reveals time-progressive accumulation of amyloid beta (Aβ) species, loss of monomeric Tau

SUBMITTER: Labra SR 

PROVIDER: S-EPMC12265565 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature