CORTICAL AND RETINAL TAUOPATHY ACROSS THE NEURODEVELOPMENT–NEURODEGENERATION CONTINUUM IN PRECLINICAL IPSC-DERIVED ORGANOID MODELS

Cortical and retinal tauopathies associated with MAPT IVS10+16 mutations offer a powerful window onto the shared mechanisms linking altered neurodevelopment to late neurodegeneration, yet how mitochondrial dysfunction intersects with tau pathology across brain and retina remains poorly defined. Here, human isogenic iPSC lines were used to generate 3D cortical organoids and 2D/3D retinal models carrying the IVS10+16 MAPT mutation, enabling parallel interrogation of tau-driven defects in neuronal–glial maturation, synaptic connectivity, and network dynamics. In both cortical and retinal systems, MAPT IVS10+16 induced an early and persistent shift toward 4R tau, increased phospho‑tau and toxic tau conformers, delayed differentiation with sustained progenitor signatures, fragmented neuritic cytoskeleton, and impaired synaptic development accompanied by reduced network synchrony and mitochondrial abnormalities. Building on the emerging concept of a neurodevelopment–neurodegeneration continuum centered on mitochondrial vulnerability, bezafibrate, a pan‑PPAR agonist and upstream activator of the PPAR–PGC‑1α–NRF1–TFAM axis, was applied to tau‑mutant cortical organoids during a critical maturation window. Bezafibrate restored mitochondrial content and transcriptional programs linked to oxidative stress and mitophagy, improved neuronal and glial maturation, rescued synaptic marker expression and glutamatergic/GABAergic balance, and normalized calcium network activity while reducing phospho‑tau burden and partially correcting 4R tau accumulation. Together, these data position cortical and retinal iPSC‑derived models as complementary, human‑relevant platforms to dissect tau‑ and mitochondria‑driven pathology, and support bezafibrate‑mediated reinforcement of mitochondrial resilience as a cross‑tissue strategy to target tauopathies along the lifespan trajectory from neurodevelopmental vulnerability to neurodegenerative decline.