Alzheimer’s Disease-like Pathological Features in the Dorsal Hippocampus of Wild-Type Rats Subjected to Methionine-Diet-Evoked Mild Hyperhomocysteinaemia

Abstract

Multifactorial interactions, including nutritional state, likely participate in neurodegeneration’s pathogenesis and evolution. Dysregulation in methionine (Met) metabolism could lead to the development of hyperhomocysteinaemia (hHcy), playing an important role in neuronal dysfunction, which could potentially lead to the development of Alzheimer’s disease (AD)-like pathological features. This study combines proton magnetic resonance spectroscopy (1H MRS) with immunohistochemical analysis to examine changes in the metabolic ratio and histomorphological alterations in the dorsal rat hippocampus (dentate gyrus—DG) subjected to a high Met diet. Male Wistar rats (420–480 g) underwent hHcy evoked by a Met-enriched diet (2 g/kg of weight/day) lasting four weeks. Changes in the metabolic ratio profile and significant histomorphological alterations have been found in the DG of hHcy rats. We have detected increased morphologically changed neurons and glial cells with increased neurogenic markers and apolipoprotein E positivity parallel with a diminished immunosignal for the N-Methyl-D-Aspartate receptor 1 in hHcy animals. A Met diet induced hHcy, likely via direct Hcy neurotoxicity, an interference with one carbon unit metabolism, and/or epigenetic regulation. These conditions lead to the progression of neurodegeneration and the promotion of AD-like pathological features in the less vulnerable hippocampal DG, which presents a plausible therapeutic target.

The Role of Methionine-Rich Diet in Unhealthy Cerebrovascular and Brain Aging: Mechanisms and Implications for Cognitive Impairment

“…Moreover, homocysteine can activate microglia, leading to neuroinflammation, another mechanism contributing to neurodegeneration [342,363]. Besides, there are indications that high methionine levels might influence the formation and aggregation of beta-amyloid plaques, a hallmark of Alzheimer's disease, further suggesting a link between methionine-rich diets and neurodegenerative processes [363][364][365][366][367][368][369][370][371][372][373][374][375]. Elevated homocysteine levels have also been associated with increased tau hyperphosphorylation, a hallmark of Alzheimer's disease [176,370].…”

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease

“…Although the triggers, underlying mechanisms, and effective treatments of AD are still unclear, recent studies have shown that dietary interventions may be potential treatment strategies (Valls-Pedret et al, 2015 ). Dietary restriction during adulthood (DR; reducing calorie intake while maintaining micronutrient levels) reduces the risk of AD (Nuru et al, 2018 ; Kovalska et al, 2023 ). Age-related impairments in learning, memory, and motor function were observed to improve in rodents undergoing dietary restriction, however the mechanics remain unclear (Xu et al, 2022 ).…”

“…High methionine diet has been proven to induce AD-like symptoms (Pi et al, 2021 ). As a dietary intervention, methionine restriction has been reported to alleviate AD, but the molecular mechanisms remain unclear (Alachkar et al, 2022 ; Kovalska et al, 2023 ; Xi et al, 2023 ). Therefore, it is of great significance to explore the specific mechanisms, by which methionine is involved in the pathogenesis of AD.…”