Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease

Abstract

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer’s disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswe/PSdE1 (APP/PS1) mice display age-related Aβ accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS+/− mice by crossing complete eNOS deficient (eNOS−/−) mice and APP/PS1 mice. APP/PS1/eNOS+/− mice at 8 months of age displayed a more severe spatial working memory deficit relative to age-matched APP/PS1 mice. Moreover, immunohistochemistry and immunoblotting revealed significantly increased Aβ plaque load in the brains of APP/PS1/eNOS+/− mice, concomitant with upregulated BACE-1 (hence increased Aβ production), downregulated insulin-degrading enzyme (hence reduced Aβ clearance) and increased immunoreactivity and expression of microglia. The present study, for the first time, demonstrated that partial eNOS deficiency exacerbated behavioral dysfunction, Aβ brain deposition, and microglial pathology in APP/PS1 mice, further implicating endothelial dysfunction in the pathogenesis of AD. The present findings also provide the scientific basis for developing preventive and/or therapeutic strategies by targeting endothelial dysfunction.

Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease

“…However, there are conflicting findings concerning the role of NOS3 in AD. For example, APP/PS1 mice with partial eNOS deficiency have a higher Aβ plaque burden in the brain compared to APP/PS1 mice at 8 months of age, and partial eNOS deficiency increases APP amyloidogenic processing [72].…”

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…Loss of micro-vascularity ( Hofer and Morey, 2018 ; Gerbie et al, 2021 ) implies an important role for cyclic/chronic hypoxic milieu ( Fine and Norman, 2008 ) in regionalizing perfusion and contributing to the progression of age-related degenerative comorbid diseases in humans. Age-related declining sex hormones (andropause/menopause) are mediated by NO–oxygen sensing ( Berchner-Pfannschmidt et al, 2007 ; Hickok et al, 2013 ), causing a hypoxic stress condition and dysregulation of the cellular biology of amyloidosis ( Cheboub et al, 2019 ; Ahmed et al, 2022 ), which is counteracted by autophagy ( Chuang et al, 2018 ; Wang and Le, 2019 ; Wang and Zhang, 2019 ), along with the epithelial-to-mesenchymal transition (EMT) ( Byrne et al, 2016 ; Kim I. et al, 2022 ; Ribatti, 2022 ; Mohamed et al, 2023 ). A regionally restricted oxygen perfusion is a cyclic/chronic hypoxic environment that can lead to degenerative pathologies such as hypertrophy, atrophy, fibrosis, and neoplasm due to developing localized hypoxia ( Figure 1 ).…”

“…However, localized cyclic/intermittent hypoxia (CIH) within a region is a potent proinflammatory stimulus in human diseases ( Schaefer et al, 2017 ; Wilson et al, 2018 ; Korbecki et al, 2021 ). Thus, advancing the establishment of a late-stage dysfunctional vasculature through vascular remodeling (receding) ( Ouarné et al, 2021 ; Ahmed et al, 2022 ; Ollonen et al, 2022 ), which would extend the “CSH compromised pulmonary circulation” region ( Böger and Hannemann, 2020 ; Prieto-Lloret et al, 2021 ) into an integrated, developing, localized CSH self-perpetuating hypovascularity cyclic/chronic hypoxia pathological microenvironment niche ( Carnero and Lleonart, 2016 ; Macharia et al, 2021 ; Frisbie et al, 2022 ) ( Figure 3 ).…”

“… 2. Nitric oxide signaling: association of endothelial dysfunction and nitric oxide signaling in the pathogenesis of Alzheimer’s disease ( Ahmed et al, 2022 ) and reduction of estrogen, which lowers nitric oxide bioavailability and induces amyloid deposition, have been observed ( Cheboub et al, 2019 ). 3.…”

Harnessing Passive Pulsatile Shear Stress for Alzheimer’s Disease Prevention and Intervention

“…Furthermore, eNO has been shown to have neurovascular protective functions that have previously been reviewed [ 66 ]. In mouse models, partial deficiency of eNOS exacerbates cognitive deficit and amyloid pathology [ 72 ], and has also been shown to increase a pro-inflammatory phenotype in the brain [ 70 ]. In contrast, high concentrations of NO produced by iNOS, produce a massive generation of peroxynitrites, oxidative stress, and NOS uncoupling with nitration of Aβ and toxicity to neurons, producing synaptic transmission impairment [ 19 ].…”