The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps.
The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps.
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DOI：
10.1016/j.exger.2010.01.001
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发表时间：
2010-04
影响因子：
3.9
通讯作者：
Maloney, Bryan
中科院分区：
文献类型：
--
作者：
Lahiri, Debomoy K.;Maloney, Bryan
神经退行性疾病阿尔茨海默病（AD）是美国第六大死亡原因。除了神经和精神症状外，AD的特征在于S-腺苷甲硫氨酸（SAM）、维生素B12和叶酸的缺乏。这些营养素的缺乏已被证明会导致基因启动子甲基化和AD相关基因的上调。虽然一些AD病例是由于早老素1（PSEN）和淀粉样β肽前体蛋白（APP）等基因的特定突变所致，但这些家族性AD（FAD）病例占少数病例。大部分遗传贡献由不完全遗传的危险因素组成。几个环境风险因素，如胆固醇和饮食，头部创伤和运动水平降低，也已确定为AD。然而，AD的大部分风险似乎在生命早期就已确定。我们建议通过LEARn（潜在的早期生活相关调节）模型来解释这一点。LEARn-AD（LAD）将是一种“两次打击”疾病，其中第一次打击将由于AD相关基因调控序列内的环境压力而发生，由表观遗传变化（如DNA甲基化）维持。这种打击很可能发生在童年早期。第二次打击可能包括进一步的压力，如头部创伤，中年饮食不良，甚至是在生命后期发生的基因表达的一般变化，而不受任何发病机制的影响。鉴于LAD的主要风险将通过DNA（低）甲基化来维持，我们建议在生命早期开始基于LEARn模型或基于LEARn的营养增益（LEARnING）的长期营养补救，将显着降低晚期AD的风险。
The neurodegenerative disorder Alzheimer’s disease (AD) is the 6th leading cause of death in the USA. In addition to neurological and psychiatric symptoms, AD is characterized by deficiencies in S–adenylmethionine (SAM), vitamin B12, and folate. Deficiency in these nutrients has been shown to result in gene promoter methylation with upregulation of AD–associated genes. While some cases of AD are due to specific mutations in genes such as presenilin 1 (PSEN) and the amyloid–β peptide precursor protein (APP), these familial AD (FAD) cases account for a minority of cases. The majority of genetic contribution consists of risk factors with incomplete penetrance. Several environmental risk factors, such as cholesterol and diet, head trauma, and reduced levels of exercise, have also been determined for AD. Nevertheless, the majority of risk for AD appears to be established early in life. We propose to explain this via the LEARn (Latent Early–life Associated Regulation) model. LEARn-AD (LAD) would be a “two-hit” disorder, wherein the first hit would occur due to environmental stress within the regulatory sequences of AD–associated genes, maintained by epigenetic changes such as in DNA methylation. This hit would most likely come in early childhood. The second hit could consist of further stress, such as head trauma, poor mid–life diet, or even general changes in expression of genes that occur later in life independent of any pathogenesis. Given that the primary risk for LAD would be maintained by DNA (hypo)methylation, we propose that long–term nutritional remediation based on the LEARn model, or LEARn–based nutritional gain (LEARnING), beginning early in life, would significantly reduce risk for AD late in life.
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DOI：
10.1016/j.jalz.2009.07.003
发表时间：
2010-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Dennis NA;Browndyke JN;Stokes J;Need A;Burke JR;Welsh-Bohmer KA;Cabeza R
通讯作者：
Cabeza R
影响因子：
4.5
作者：
Lahiri DK;Zawia NH;Greig NH;Sambamurti K;Maloney B
通讯作者：
Maloney B
影响因子：
3.5
作者：
Fuso, A;Seminara, L;Scarpa, S
通讯作者：
Scarpa, S
影响因子：
3.5
作者：
Fuso, Andrea;Nicolia, Vincenzina;Scarpa, Sigfrido
通讯作者：
Scarpa, Sigfrido
影响因子：
5.3
作者：
Christensen, MA;Zhou, WH;Song, WH
通讯作者：
Song, WH