Aβ-independent roles of the amyloid precursor protein in Alzheimer’s disease pathogenesis.
My research investigates how the amyloid precursor protein (APP) holoprotein itself—rather than its processed amyloid-beta fragments—contributes to neurodegeneration in Alzheimer’s disease. While the field has traditionally centered on Aβ plaques as the primary driver of disease, my work challenges this paradigm by examining APP’s direct effects on neuronal structure and function. I have shown that elevated APP levels, whether induced by glutamate exposure, APP overexpression, or an APP transgene, cause the axon initial segment to shorten and shift position away from the cell body, changes that are associated with a predicted decrease in neuronal network activity. These structural alterations in the axon initial segment represent a novel, amyloid-independent mechanism by which APP dysregulation can impair neuronal signaling well before plaque pathology emerges. Related work from my time in the Herrup lab also examined how DNA damage accumulates in the oligodendrocyte lineage during brain aging, showing that oligodendrocytes are uniquely vulnerable to oxidative DNA damage and that unrepaired damage impairs myelin gene transcription and differentiation.
The overarching goal of my research program is to build a more comprehensive mechanistic model of Alzheimer’s disease that helps explain why decades of amyloid-targeting therapies have failed to succeed clinically, and to identify novel therapeutic targets grounded in this revised understanding of APP biology.
Representative Publications
Behavior of neural networks in culture suggest that sporadic and genetic forms of Alzheimer's disease may not be equivalent
Fulin Ma, Himanshu Akolkar, Ryad Benosman, Karl Herrup
Journal of the Alzheimer's Association (2026)
Effects of damaged astrocytes on DNA damage and repair in human neurons: Implications for Alzheimer's disease
Starr Welty, Michael Bagnell, Fulin Ma, Karl Herrup, Arthur Samuel Levine
Journal of Alzheimer's Disease (2026)
APP and DNA damage create a feedforward loop that contributes to Alzheimer's disease pathogenesis
Fulin Ma, R Kingston, E Brenner, Karl Herrup
Journal of the Alzheimer's Association (2025)
The interaction between aging and DNA damage influences the accumulation of APP in Alzheimer's disease
Eliana Brenner, Gnanesh Gutta, Fiona Stauffer, Jay Mehta, Rody Kingston, Michael Bagnell, Starr Welty, Natalie Dixon, Elizabeth Zinzell, Karl Herrup Fulin Ma
BioRxiv (2025)
DNA damage and senescence in the aging and Alzheimer’s disease cortex are not uniformly distributed
Karl Herrup, Gnanesh Gutta, Jay Mehta, Rody Kingston, Fulin Ma
Journal of the Alzheimer's Association (2024)
White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells
Sunny Hoi-Sang Yeung, Ralph Hon-Sun Lee, Gerald Wai-Yeung Cheng,Iris Wai-Ting Ma, Julia Kofler, Candice Kent, Fulin Ma, Karl Herrup, Myriam Fornage, Ken Arai, Kai-Hei Tse
Federation of American Societies for Experimental Biology (2024)
DNA damage and senescence in the aging and Alzheimer’s disease cortex are not uniformly distributed
Karl Herrup, Gnanesh Gutta, Jay Mehta, Rody Kingston, Fulin Ma
Biomedicines (2024)
White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells
Sunny Hoi-Sang Yeung, Ralph Hon-Sun Lee, Gerald Wai-Yeung Cheng,Iris Wai-Ting Ma, Julia Kofler, Candice Kent, Fulin Ma, Karl Herrup, Myriam Fornage, Ken Arai, Kai-Hei Tse
BioRxiv (2023)
The amyloid precursor protein modulates the position and length of the axon initial segment
Fulin Ma, Himanshu Akolkar, Jianquan Xu, Yang Liu, Dina Popova, Jiaan Xie, Mark M. Youssef, Ryad Benosman, Ronald P. Hart and Karl Herrup
The Journal of Neuroscience (2023)
The amyloid precursor protein modulates the position and length of the axon initial segment offering a new perspective on Alzheimer’s disease genetics
Fulin Ma, Jianquan Xu, Yang Liu, Dina Popova, Mark M Youssef, Ronald P Hart, Karl Herrup
BioRxiv (2022)
A new look at Alzheimer's genetics: APP dampens neuronal excitability by regulating the size and cellular location of the axon initial segment
Fulin Ma, H Akolkar, Karl Herrup, Ryad Benjamin Benosman
Journal of the Alzheimer's Association (2022)
DNA damage-induced neuroinflammation in neurodegenerative disease
Xuan Song, Fulin Ma, Karl Herrup
Journal of the Alzheimer's Association (2022)
DNA repair inhibition leads to active export of repetitive sequences to the cytoplasm triggering an inflammatory response
Xuan Song, Jacqueline T. M. Aw, Fulin Ma, Ming Fung Cheung, Danny Leung, Karl Herrup
The Journal of Neuroscience (2021)
ATM loss disrupts the autophagy-lysosomal pathway
Aifang Chen, Kai-Hei Tse, Hei-Main Chow, Yunqiao Gan, Xuan Song, Fulin Ma, Yi Xuan Yvonne Qian, Weiyi She, Karl Herrup
Authophagy (2021)
Identifying a population of glial progenitors that have been mistaken for neurons in embryonic mouse cortical culture
Yang Zhang, Beika Zhu, Fulin Ma, Karl Herrup
eNeuro (2021)
DNA damage induced neuroinflammation in neurodegenerative disease: Developing topics
Xuan Song, Theeng Mei AW, Fulin Ma, Danny Leung, Karl Herrup
Journal of the Alzheimer's Association (2020)
Inactivation of Escherichia coli O157: H7 in apple cider by resveratrol and naringenin
Meera Surendran Nair, Fulin Ma, Patrick Lau, Indu Upadhyaya, Kumar Venkitanarayanan
ScienceDirect (2020)