Novel amyloid-β filament fold in individuals with APP Flemish mutation
Dr. Peerzada Shariq Shaheen Khaki (Post-doctoral Fellow)
[Supervisor: Professor Ruben Hervas Millan]

The dominantly inherited Flemish mutation—an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)—causes a rare, early-onset form of Alzheimer’s disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-EM structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide. While a minority of tau paired helical filaments were present, the predominant filaments comprise A21G Aβ40, assembled as two identical protofilaments (D1–V40) packed with 2-start helical symmetry. A21G Aβ40 and wild-type Aβ42 filaments share a substructure preceding the mutation (Y10–F19); however, loss of the methyl group at position 21 in the Flemish variant triggers a structural rearrangement yielding a novel 'Flemish fold', distinct from all previously characterized Aβ folds and defined by a unique hydrophobic interface. Using a cell-based assay, we find that this distinctive fold is linked to the vascular tropism characteristic of the Flemish variant. These findings reveal a new amyloid fold linked to familial Alzheimer’s disease, advancing our understanding of the molecular basis of Flemish-type dementia and cerebral hemorrhage.

Regulatory functions of FACI and FACI-like proteins in lipid homeostasis
Dr. Yun Cheng (Post-doctoral Fellow)
[Supervisor: Professor Dong-Yan Jin]

CREB-H (cAMP-responsive element-binding protein, Hepatic) is a liver- and intestine-enriched transcription factor that orchestrates key aspects of lipid metabolism. We identified the fasting- and CREB-H-induced (FACI) gene, also known as C11orf86, as a direct transcriptional target of CREB-H. FACI is localized to the plasma membrane (PM), where it is either evenly distributed or concentrated within clathrin-coated pits (CCPs). FACI contains five conserved regions (Motifs A–E). Motif E forms an amphipathic α-helix that functions as a phosphoinositide (PI)-binding module mediating PM localization of FACI, whereas motif D (DxxxLI) is an acidic dileucine motif that directs FACI to CCPs. Phosphorylation of motifs A and C by PKCα causes FACI to dissociate from CCPs. Functionally, FACI enhances clathrin-mediated low-density lipoprotein (LDL) uptake. Hepatic overexpression of FACI alleviates diet-induced hypercholesterolemia in mice. We further identified C1orf115 as a FACI-like protein. Like FACI, C1orf115 contains an amphipathic α-helix that confers phosphoinositide binding and PM localization, as well as an acidic dileucine-like signal (ExxxIL) that mediates CCP targeting. In contrast to FACI’s role in LDL uptake, C1orf115 induces ABCA1 transcription to drive cholesterol efflux.

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