The Effect Of Menin On HSD11β1 And Its Implication In The Pathogenesis Of Alzheimer’s Disease

Alzheimer’s disease(AD)is the most common neurodegenerative disease,accounting for about two-thirds of all dementia patients.AD patients generally exhibit neuropsychiatric disorders such as cognitive memory impairment,language and logic impairment,and affective disorders,which seriously affect patients’ normal communication and impose a heavy burden on patients,families and society.The pathogenic mechanisms of AD are not yet clearly elucidated,and there is a lack of clinically targeted prevention and treatment drugs.At present,the mainstream view is that the senile plaques formed by β-amyloid accumulation in the brain of AD patients and the neurofibrillary tangles caused by microtubule-related protein Tau hyperphosphorylation are the main factors causing cognitive and memory impairment in AD patients,but the development of new drugs for β-amyloid and Tau hyperphosphorylation has not been successful.Therefore,we urgently need to study the development process of AD from other perspectives,explain the pathogenic mechanism of AD,and provide new ideas and new targets for the development of new drugs for AD.Aging is a process that all life goes through,and it is an inevitable and irreversible natural law.All functions of the body are damaged to different degrees during the aging process,and aging is also one of the important factors affecting the pathological development of AD.In elderly people,especially AD patients,various stresses in their life and pathological lesions in the brain lead to a chronic stressful condition in the brain of AD patients.Under chronic stress conditions,the stress hormone glucocorticoid is activated in the brain and may be involved in the pathogenic process of AD.Glucocorticoid is a stress hormone regulated by the Hypothalamic-pituitary-adrenal axis(HPA Axis).When the body is under stress,the HPA axis activity increases,promoting the release of glucocorticoids from the adrenal cortex to help cope better with stress.The brain is very sensitive to glucocorticoid,and in AD patients,senile plaques and neurofibrillary tangles in the brain promote glucocorticoid production and activation.The over-activated glucocorticoids impair synaptic plasticity,exacerbating cognitive memory impairment in AD patients.Glucocorticoids are regulated by two main pathways.Glucocorticoid synthesis is regulated by the HPA axis,while intracellular glucocorticoid concentrations are regulated by Hydroxysteroid 11-β Dehydrogenase 1(HSD11β1).HSD11β1 converts the inactive glucocorticoid corticosterone into active cortisol in cells.During aging,abnormally elevated levels of HSD11β1 in the mouse brain lead to an over-activation of the glucocorticoid in neuronal cells,causing a decline in cognitive memory.However,the mechanisms of how HSD11β1 expression is regulated in the brain are not yet clear.The Multiple Endocrine Neoplasia Ⅰ syndrome(MEN1)is a gene closely associated with a variety of endocrine tumors and expresses the protein Menin,a co-transcription factor that promotes the transcription of a variety of tumor suppressors.Menin plays an important regulatory role in the neuroendocrine system,it is possible that Menin is directly involved in the regulation of glucocorticoid levels by the HPA axis.Our previous study showed that the serum levels of glucocorticoids were elevated in MEN1 knockout mice,suggesting that Menin is involved in the regulation of glucocorticoid levels.This paper focuses on studies to investigate the effects of Menin on HSD11β1 expression levels as well as intracellular glucocorticoid levels.We have systematically investigated and elucidated the molecular mechanisms directly involved in the transcriptional regulation of HSD11β1 by Menin through MEN1 neurological conditional knockout mice.We found that in the brains of AD mice,Menin expression was reduced,while HSD11β1 expression was activated,exacerbating glucocorticoid overactivation in neuronal cells and leading to impairment of cognitive memory.Our study elucidates the mechanism of Menin regulation of HSD11β1 during AD pathogenesis,providing a new research target for the regulatory role of glucocorticoids in AD and a new direction for the development of drugs to prevent and treat neurodegenerative diseases such as AD.