PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model
Abstract
Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer’s disease (AD), yet its role in amyloid-beta (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive enzyme-linked immunosorbent assay, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric Aβ 1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein and BACE1 levels, altered γ-secretase complex composition, and enhanced Aβ degradation via neprilysin. These findings position PARP1 as a critical mediator of Aβ toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Aanishaa Jhaldiyal
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Manisha Kumari
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Lauren C. Guttman
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Trupti Tripathi
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Mohammed Repon Khan
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Justin Wang
Devanik Biswas
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Abhishek Pasupuleti
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Akansha Aggarwal
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Shraddha Pandya
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Shih-Ching Chou
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Nikhil Panicker
Abhay Monghekar
Department of Neurology, The Johns Hopkins University School of Medicine
Marilyn Albert
Lynn M. Bekris
Department of Laboratory Medicine and Pathology, University of Washington
James B. Leverenz
Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic
Tae-In Kam
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
Ted M. Dawson
Valina L. Dawson