The neural nitric oxide synthase is associated with cognitive decline and Alzheimer’s disease pathology

Abstract

AbstractBackgroundAlthough Alzheimer’s disease (AD) etiology is partially explained by the deposition of aggregated forms of β‐amyloid proteins and neurofibrillary tangles in the brain, the process that triggers the deposition of these proteins is still unknown. The neural (nNOS), endothelial (eNOS), and inducible nitric oxide synthases (iNOS) may play an important role in AD pathophysiology according to previous studies in animals. However, studies on humans are scarce. Therefore, we aimed to quantify the expression of NOS enzymes in the hippocampus of individuals with AD compared to individuals without the disease and investigate the association of NOS expression with cognition and AD‐related pathology.MethodWe evaluated the nNOS, eNOS, and iNOS expressions using immunohistochemistry in the cornu ammonis (CA) and the dentate gyrus (DG) from hippocampi from subjects with pure AD and sex‐matched controls. Cognitive abilities were evaluated using the Clinical Dementia Rating (CDR) and AD pathology using Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) for neuritic plaque. We used linear regression to examine the association of NOS with cognition and AD pathology.ResultsSociodemographic and clinical variables were similar between the control and AD groups (Table 1). In individuals with AD, nNOS was overexpressed in the CA (β = 23.62, IC95% = 5.13;42.10, p = 0.01) and DG (β = 16.76, IC95% = 0.35;3.18, p = 0.01), while eNOS and iNOS were increased only in the CA (β = 0.93, IC95% = 0.02;1.84, p = 0.04; β = 0.19, IC95% = 0.09;0.90, p = 0.01, respectively) (Figure 1). Larger nNOS levels in the CA and DG were associated with worse cognitive abilities, higher Braak and CERAD scores (Table 2).ConclusionThe nNOS, eNOS, and iNOS were increased in the hippocampi of subjects with AD. However, only nNOS overexpression was associated with cognitive impairment and AD‐related pathology.