Abstract
The neuropathology of Parkinson’s disease with dementia (PDD) has been reported to involve heterogeneous and various disease mechanisms. Alpha-synuclein (α-syn) and amyloid beta (Aβ) pathology are associated with the cognitive status of PDD, and NADPH oxidase (NOX) is known to affect a variety of cognitive functions. We investigated the effects of NOX on cognitive impairment and on α-syn and Aβ expression and aggregation in PDD. In the 6-hydroxydopamine (6-OHDA)-injected mouse model, cognitive and motor function, and the levels of α-syn, Aβ, and oligomer A11 after inhibition of NOX4 expression in the hippocampal dentate gyrus (DG) were measured by the Morris water maze, novel object recognition, rotation, and rotarod tests, as well as immunoblotting and immunohistochemistry. After 6-OHDA administration, the death of nigrostriatal dopamine neurons and the expression of α-syn and NOX1 in the substantia nigra were increased, and phosphorylated α-syn, Aβ, oligomer A11, and NOX4 were upregulated in the hippocampus. 6-OHDA dose-dependent cognitive impairment was observed, and the increased cognitive impairment, Aβ expression, and oligomer A11 production in 6-OHDA-treated mice were suppressed by NOX4 knockdown in the hippocampal DG. Our results suggest that increased expression of NOX4 in the hippocampal DG in the 6-OHDA-treated mouse induces Aβ expression and oligomer A11 production, thereby reducing cognitive function.
Highlights
Parkinson’s disease (PD) is a common progressive neurodegenerative disease
For the first time, that this cognitive impairment was mediated by the expression and aggregation of Aβ in the hippocampus and was associated with an increase in NOX4 expression in the hippocampal dentate gyrus (DG)
Hippocampal Aβ expression, A11 oligomer formation, and cognitive impairment were attenuated by genetic interventions targeting NOX4 in the hippocampal DG
Summary
Parkinson’s disease (PD) is a common progressive neurodegenerative disease. The main neuropathological feature of PD is the loss of dopaminergic neurons [1]. Parkinson’s neuropathology with dementia (PDD) is heterogeneous and involves several disease mechanisms [3]. Despite the central role of α-syn pathology in PDD, some studies have found that Aβ plaques and tau neurofibrillary tangles, a characteristic pathological cause of Alzheimer disease (AD), are related to the cognitive status of PDD [4,5,6,7,8,9]. Neuropathological examinations using a recently developed molecular imaging approach showed that the production of amyloid plaques is common in PDD with Lewy body dementia [5,10,11,12,13,14]. In 50% of patients with PDD, Aβ plaques and tau-containing nerve fibers are entangled, which can aggravate the prognosis of disease via synergism with α-syn pathology [4]
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