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