A model of lipid dysregulation and altered nutrient status in Alzheimer's disease

Abstract

Introduction Dysregulated lipid metabolism and nutrient status are thought to play a role in the pathophysiology of Alzheimer's disease (AD). However, the precise involvement is not well understood, and it remains unclear exactly how such dysregulated lipid metabolism and altered nutrient status, especially changes in phosphatidylcholine, B12, and folate, are connected to the hallmark pathology in AD (i.e., amyloidogenesis). Methods We have postulated that genetic susceptibility (i.e., APOE ε4/ε4) to environmental exposure to emissions of nitrous oxide (N 2 O) could underlie the onset of AD and its early neuropsychiatric correlates Results and Discussion The current theoretical editorial describes, using clinical, preclinical, and in vitro evidences, how this model contributes not only to amyloidogenesis but also other nonopioid effects, specifically altered lipid metabolism, depletion of vitamin B12, and disruption of the folate-mediated one carbon metabolic pathway.

Herpes simplex virus reactivation and the relationship with Alzheimer's disease: A countering view

“…N 2 O is widely used as a mild anesthetic adjuvant in medicine, but the compound has a critical duality in that it is also pervasive in the environment as an air pollutant derived, primarily, from the use of anthropogenic nitrogen in agriculture. Our 2019 editorial in Alzheimer's & Dementia draws parallels from the experimental effects of N 2 O on folate‐mediated one‐carbon metabolism (creating B 12 and folate deficiencies), lipid dysregulation, and modulation of caspase activation to the altered nutrient status and lipodome, which are present in AD . Also, many of the clinical impairments and conditions induced from N 2 O exposure are considered to be strong risk factors or diagnostic prognosticators for neurodegeneration and, specifically, AD .…”

“…It has been postulated that genetic susceptibility to environmental exposure to emissions of nitrous oxide (N 2 O) could underlie the onset of AD (See PubMed Bibliography at https://www.ncbi.nlm.nih.gov/myncbi/1r5h3UjOlyj5q/bibliography/public/) . N 2 O is widely used as a mild anesthetic adjuvant in medicine, but the compound has a critical duality in that it is also pervasive in the environment as an air pollutant derived, primarily, from the use of anthropogenic nitrogen in agriculture.…”

“…As HSV‐1 has been shown to deplete DYN A‐like immunoreactivity in the hippocampus in a rat model of HSV‐1 encephalitis, it is suggested that HSV reactivation in AD reverses the non‐opioid, DYN‐induced cascade leading to neuronal loss (i.e. trace N 2 O exposure‐induced DYN release and caspase activation → nicotinic acetylcholine receptor inhibition → oxidative stress/amyloidogenesis) and therefore represents a compensatory mechanism to salvage neuronal health.…”

“…Our 2019 editorial in Alzheimer's & Dementia draws parallels from the experimental effects of N 2 O on folate-mediated onecarbon metabolism (creating B 12 and folate deficiencies), lipid dysregulation, and modulation of caspase activation to the altered nutrient status and lipodome, which are present in AD. 3 Also, many of the clinical impairments and conditions induced from N 2 O exposure are considered to be strong risk factors or diagnostic prognosticators for neurodegeneration and, specifically, AD. 3 Related most specifically to amyloidogenesis, in vitro evidence has shown that N 2 O induces caspase-3 activation in H4-na€ ıve cells stably-transfected to express full-length amyloid precursor protein.…”

“…3 Also, many of the clinical impairments and conditions induced from N 2 O exposure are considered to be strong risk factors or diagnostic prognosticators for neurodegeneration and, specifically, AD. 3 Related most specifically to amyloidogenesis, in vitro evidence has shown that N 2 O induces caspase-3 activation in H4-na€ ıve cells stably-transfected to express full-length amyloid precursor protein. 7 This property might be related to the N 2 O-induced endogenous release of dynorphin (DYN) in the rat brain, and activation of its cognate opioid receptor, the kappa opioid receptor (KOR), especially at the lower drug doses before higherorder mechanisms have been activated.…”