PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model
11 affiliations
- 1Department of Neurology, The Johns Hopkins University School of Medicine
- 2Department of Physiology, Pharmacology and Therapeutics, The Johns Hopkins University School of Medicine
- 3Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine
- 4Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University School of Medicine
- 5Department of Laboratory Medicine and Pathology, University of Washington
- 6Lerner Research Institute, Genomic Medicine, Cleveland Clinic
- 7Department of Neurology, Cleveland Clinic
- 8Department of Neurology, University of Washington
- 9Geriatric Research Education and Clinical Center, Veteran Affairs Puget Sound Health Care System (S-182)
- 10Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic
- 11Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine
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-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, 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 (APP) 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. Significance Statement Our study identifies poly(ADP-ribose) (PAR) as an elevated biomarker in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimer’s disease, correlating with established markers of amyloid pathology. We demonstrate that PARP1, the enzyme responsible for PAR synthesis, is activated by neurotoxic Aβ 1-42 and mediates neuronal death, amyloid plaque formation, neuroinflammation, and cognitive deficits in a mouse model of AD. Importantly, genetic ablation of PARP1 not only protects neurons from Aβ toxicity but also reduces amyloid burden by suppressing Aβ production and enhancing its degradation. These findings highlight PARP1 as a critical regulator of amyloid pathology and neurodegeneration, and suggest that PARP1 inhibition may offer a promising therapeutic avenue for Alzheimer’s disease by simultaneously targeting multiple pathogenic mechanisms.
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BibTeX
@article{jhaldiyal2026parp1,
title = {{PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model}},
author = {Aanishaa Jhaldiyal and Manisha Kumari and Lauren C. Guttman and Trupti Tripathi and Mohammed Repon Khan and Justin Wang and Devanik Biswas and Abhishek Pasupuleti and Akansha Aggarwal and Shraddha Pandya and Shih-Ching Chou and Nikhil Panicker and Abhay Monghekar and Marilyn Albert and Lynn M. Bekris and James B. Leverenz and Tae‐In Kam and Ted M. Dawson and Valina Lynn Dawson},
journal = {Proceedings of the National Academy of Sciences},
year = {2026},
month = may,
doi = {10.1073/pnas.2525028123},
url = {https://doi.org/10.1073/pnas.2525028123},
note = {CC BY},
}
RIS
TY - JOUR
TI - PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model
AU - Aanishaa Jhaldiyal
AU - Manisha Kumari
AU - Lauren C. Guttman
AU - Trupti Tripathi
AU - Mohammed Repon Khan
AU - Justin Wang
AU - Devanik Biswas
AU - Abhishek Pasupuleti
AU - Akansha Aggarwal
AU - Shraddha Pandya
AU - Shih-Ching Chou
AU - Nikhil Panicker
AU - Abhay Monghekar
AU - Marilyn Albert
AU - Lynn M. Bekris
AU - James B. Leverenz
AU - Tae‐In Kam
AU - Ted M. Dawson
AU - Valina Lynn Dawson
PY - 2026
DA - 2026/05/15
JO - Proceedings of the National Academy of Sciences
DO - 10.1073/pnas.2525028123
UR - https://doi.org/10.1073/pnas.2525028123
AB - 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-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, 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 (APP) 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. Significance Statement Our study identifies poly(ADP-ribose) (PAR) as an elevated biomarker in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimer’s disease, correlating with established markers of amyloid pathology. We demonstrate that PARP1, the enzyme responsible for PAR synthesis, is activated by neurotoxic Aβ 1-42 and mediates neuronal death, amyloid plaque formation, neuroinflammation, and cognitive deficits in a mouse model of AD. Importantly, genetic ablation of PARP1 not only protects neurons from Aβ toxicity but also reduces amyloid burden by suppressing Aβ production and enhancing its degradation. These findings highlight PARP1 as a critical regulator of amyloid pathology and neurodegeneration, and suggest that PARP1 inhibition may offer a promising therapeutic avenue for Alzheimer’s disease by simultaneously targeting multiple pathogenic mechanisms.
SN - 0027-8424
SN - 1091-6490
ER -