SFRP1 REGULATION OF CHOROID PLEXUS FUNCTION IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder associated with the overproduction of amyloid-beta (Aβ) peptides and defective Aβ clearance. Extracellular accumulation of Aβ leads to amyloid plaque formation, followed by intracellular tau hyperphosphorylation and aggregation into toxic neurofibrillary tangles. Multiple factors involved in Aβ production and metabolism may contribute to disease onset. Among these, Secreted Frizzled-Related Protein 1 (SFRP1) accumulates in the brains and cerebrospinal fluid (CSF) of AD patients and negatively regulates ADAM10, a protease involved in non-amyloidogenic APP processing. Elevated SFRP1 levels stabilize toxic Aβ species, exacerbate neuroinflammation, and impair synaptic plasticity. In the adult brain, the choroid plexus (CP)—a structure responsible for CSF production and clearance—is a major source of SFRP1. CP dysfunction may compromise Aβ clearance and contribute to its accumulation in the brain. In this context, we are studying whether and how SFRP1 affects CP function during AD pathology. We have performed transcriptomic analyses of CP tissue from wild-type (WT), APP/PS1, and APP/PS1-Sfrp1 knockout mice to identify AD-related transcriptional changes associated with variable SFRP1 expression. In parallel, we are generating CP organoids from human induced pluripotent stem cells (iPSCs) carrying either the ApoE3 or ApoE4 isoforms, which have been proposed to interact with SFRP1. Furthermore, ApoE4 is a well-established AD genetic risk factor, present in approximately 37% of sporadic AD patients and highly expressed in the CP. Integrating these experimental approaches, we expect to establish the potential relationship between ApoE isoforms, SFRP1 in the CP and their contribution to AD.