Poly(adp-ribose) polymerase 1 deficiency attenuates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer disease model

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA
damage responses and neuroinflammation in Alzheimer 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.