Applying Epigenetics to Alzheimer’s Disease via the Latent Early–life Associated Regulation (LEARn) Model

Abstract

Alzheimer's disease (AD) is a leading cause of aging related dementia and has been extensively studied by several groups around the world. A general consensus, based on neuropathology, genetics and cellular and animal models, is that the 4 kDa amyloid β protein (Aβ) triggers a toxic cascade that induces microtubule-associated protein τ (MAPT) hyperphosphorylation and deposition. Together, these lesions lead to neuronal dysfunction and neurodegeneration, modeled in animals, that ultimately causes dementia. Genetic studies show that a simple duplication of the Aβ precursor (APP) gene, as occurs in Down syndrome (trisomy 21), with a 1.5-fold increase in expression, can cause dementia with the complete AD associated neuropathology. The most fully characterized form of AD is early onset familial AD (FAD). Unfortunately, by far the most common form of AD is late onset AD (LOAD). FAD has well-identified autosomally dominant genetic causes, absent in LOAD. It is reasonable to hypothesize that environmental influences play a much stronger role in etiology of LOAD than of FAD. Since AD pathology in LOAD closely resembles FAD with accumulation of both Aβ and MAPT, it is likely that the environmental factors foster accumulation of these proteins in a manner similar to FAD mutations. Therefore, it is important to identify environmentally driven changes that "phenocopy" FAD in order to find ways to prevent LOAD. Epigenetic changes in expression are complex but stable determinants of many complex traits. Some aspects are regulated by prenatal and early post-natal development, others punctuate specific periods of maturation, and still others occur throughout life, mediating predictable changes that take place during various developmental stages. Environmental agents such as mercury, lead, and pesticides can disrupt the natural epigenetic program and lead to developmental deficits, mental retardation, feminization, and other complex syndromes. In this review we discuss latent early- life associated regulation (LEARn), where apparently temporary changes, induced by environmental agents, become latent and present themselves again at maturity or senescence to increase production of Aβ that may cause AD. The model provides us with a novel direction for identifying potentially harmful agents that may induce neurodegeneration and dementia later in life and provides hope that we may be able to prevent age-related neurodegenerative disease by "detoxifying" our environment.

The ‘golden age’ of DNA methylation in neurodegenerative diseases

“…A second example is given by the studies about the theory, abovementioned, that epigenetic changes may occur in the early life but become manifest in elderly. This theory in AD research has provided a fertile and rich field of intense study which developed the definition of the LEARn (Latent Early-life Associated Regulation) model [ 91 ]. According to this theory, environmental factors could poison the genome via epigenetic marks in the early phases of life, possibly even during the life in utero.…”

NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure

“…Familial AD cases account for only a small proportion of total AD cases, with the vast majority of cases being sporadic or late onset (Marques et al, 2010). The molecular and cellular mechanisms involved in the cascade of events that lead to AD remain to be resolved, but accumulating evidence suggests that the etiology of late-onset AD is multifactorial and consists of interactions between environmental factors and genetic predisposition (Bakulski et al, 2012;Bertram et al, 2010;Guerreiro et al, 2012;Maloney et al, 2012;Moulton and Yang, 2012). Although great progresses have been made over the previous years in elucidating the genetic causes of AD, our understanding of the environmental factors for AD remain very limited.…”

Elevation of Peripheral BDNF Promoter Methylation Links to the Risk of Alzheimer's Disease

“…As a link between genetic and environmental factors, epigenetic modification is able to cause stunted growth, mental retardation, feminization, and other complex syndromes [7], [8]. Genes with aberrant DNA methylation could change gene expression levels [9], and thus, might contribute to the risk of diseases or disorders such as coronary heart disease [10], [11], essential hypertension [12], schizophrenia [9], leukemia [13] and type 2 diabetes [7], [14].…”