Alzheimer's disease (AD) is a leading cause of mortality in the elderly and is characterized by a complex and multifactorial etiology. While large-scale genetic studies have identified over 50 genes and thousands of risk variants in AD, the regulatory mechanisms through which most of these factors drive pathogenesis remain poorly understood, and effective treatments are still lacking. Our research integrates stem cell modeling, genome editing, and whole-brain AAV delivery technologies to dissect the mechanistic contributions of genetic risk factors to AD pathogenesis and to develop precision gene therapies capable of correcting pathogenic genetic alterations at the whole-brain level.

Pathogenesis and gene therapy of Alzheimer's disease

1. Li M#, Guan M#, Lin J#, Zhu K#, Zhu J, Guo M, Li Y, Chen Y, Chen Y, Zou Y, Wu D, Xu J, Yi W, Fan Y, Ma S, Chen Y, Xu J, Yang L, Dai J, Ye T*, Lu Z*, Chen Y*. Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer's disease. Alzheimers Dement. 2024; 20(8):5492-5510.

2. Yi R#, Chen S#, Guan M, Liao C, Zhu Y, Ip JPK, Ye T*, Chen Y*. A single-cell transcriptomic dataset of pluripotent stem cell-derived astrocytes via NFIB/SOX9 overexpression. Sci Data. 2024, 11(1): 987.

3. Guan M#, Chai Y#, Yi R, Chen Y, Ip JPK, Ye T*, Chen Y*. Generation of a homozygous ABCA7-knockout human iPSC line using the CRISPR/Cas9 system. Stem Cell Res. 2023, 66: 103000.

4. Duan Y#, Ye T#, Qu Z, Chen Y, Miranda A, Zhou X, Lok KC, Chen Y, Fu AKY, Gradinaru V, Ip NY. Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer's disease alleviates amyloid-related pathologies in mice. Nat Biomed Eng. 2022, 6(2): 168-180.

5. Ye T, Duan Y, Tsang HWS, Xu H, Chen Y, Cao H, Chen Y, Fu AKY, Ip NY. Efficient manipulation of gene dosage in human iPSCs using CRISPR/Cas9 nickases. Commun Biol. 2021, 4(1): 195.

6. Ye T, Ip JPK, Fu AKY, Ip NY. Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex. Nat Commun. 2014, 5: 4826.