Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model

Jhaldiyal, A.; Kumari, M.; Tripathi, T.; Khan, R.; Wang, J.; Guttman, L.; Biswas, D.; Pasupuleti, A.; Aggarwal, A.; Pandya, S.; Chou, S.-C.; Panicker, N.; Monghekar, A.; Albert, M.; Bekris, L.; Leverenz, J.; Kam, T.-I.; Dawson, T.; Dawson, V. L.

doi:10.1101/2025.09.06.674313

bioRxiv · 10.1101/2025.09.06.674313

Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model

Jhaldiyal, A.·Kumari, M.·Tripathi, T.·Khan, R.·Wang, J.·Guttman, L.·Biswas, D.·Pasupuleti, A.·Aggarwal, A.·Pandya, S.·Chou, S.-C.·Panicker, N.·Monghekar, A.·Albert, M.·Bekris, L.·Leverenz, J.·Kam, T.-I.·Dawson, T.·Dawson, V. L.

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Abstract

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimers disease (AD), yet its role in amyloid-{beta} (A{beta}) pathology remains unclear. Here, we show that PARP1 activation drives A{beta} 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 A{beta}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 {gamma}-secretase complex composition, and enhanced A{beta} degradation via neprilysin. These findings position PARP1 as a critical mediator of A{beta} toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD. Significance StatementOur study identifies poly(ADP-ribose) (PAR) as an elevated biomarker in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimers disease, correlating with established markers of amyloid pathology. We demonstrate that PARP1, the enzyme responsible for PAR synthesis, is activated by neurotoxic A{beta}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 A{beta} toxicity but also reduces amyloid burden by suppressing A{beta} 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 Alzheimers disease by simultaneously targeting multiple pathogenic mechanisms.

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Jhaldiyal, A., Kumari, M., Tripathi, T., Khan, R., Wang, J., Guttman, L., Biswas, D., Pasupuleti, A., Aggarwal, A., Pandya, S., Chou, S.-C., Panicker, N., Monghekar, A., Albert, M., Bekris, L., Leverenz, J., Kam, T.-I., Dawson, T., Dawson, V. L.. 2025-09-07. Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model. https://doi.org/10.1101/2025.09.06.674313

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