Cognitive dysfunction in Parkinson's disease: Hippocampal vulnerability and redox-driven mechanisms.

Authors

Ana Rita Curto, Ana Alexandra Silva, Mariana Bernardo Fiadeiro, Dina Pereira, Ana Clara Cristóvão

Published in

Redox biology. Volume 96. Pages 104318. Jul 20, 2026. Epub Jul 20, 2026.

Abstract

Cognitive dysfunction is one of the most disabling non-motor manifestations of Parkinson's disease (PD), progressing from mild cognitive impairment to Parkinson's disease dementia. Although multiple pathological processes have been individually implicated, the mechanisms linking neurotransmitter deficits, proteinopathies, circuit vulnerability, and neurodegeneration remain insufficiently integrated. Here, we synthesize current evidence on the pathophysiology of cognitive impairment in PD, emphasizing the convergence of dopaminergic, cholinergic, noradrenergic and serotonergic dysfunction with α-synuclein, tau and amyloid-β pathology. We highlight the hippocampus - particularly the CA2 subregion - as a critical anatomical hub connecting synaptic dysfunction, memory impairment, and dementia progression. Accumulating evidence identifies oxidative stress and neuroinflammation as central drivers across these pathological domains. Among endogenous sources of reactive oxygen species, NADPH oxidases (NOX), especially Nox4, emerge as key regulators of redox imbalance, protein aggregation and glial-neuronal interactions. Increased Nox4 activity correlates with hippocampal damage and cognitive decline, whereas experimental inhibition of Nox4 preserves synaptic integrity and improves memory performance in preclinical models. By integrating molecular, cellular and systems-level findings, this review positions redox dysregulation - and NOX-dependent signaling in particular - as a unifying mechanism underlying cognitive decline in PD, and discusses emerging therapeutic strategies targeting redox pathways, highlighting NOX modulation as a promising approach to modify the course of Parkinson's disease-associated cognitive impairment.

PMID:
42485748
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.

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