Applying epigenetics to alzheimer's disease via the latent early-life associated regulation (LEARn) model

Bryan Maloney, Kumar Sambamurti, Nasser Zawia, Debomoy Lahiri

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)589-599
Number of pages11
JournalCurrent Alzheimer Research
Volume9
Issue number5
StatePublished - Jun 2012

Fingerprint

Epigenomics
Alzheimer Disease
Dementia
Microtubule-Associated Proteins
Down Syndrome
Hope
Feminization
Serum Amyloid A Protein
Poisons
Genetic Models
Mercury
Pesticides
Intellectual Disability
Neurodegenerative Diseases
Consensus
Animal Models
Pathology
Mutation
Genes
Proteins

Keywords

  • Alzheimer
  • Envirome
  • Environment
  • Epigenetics
  • Epigenome
  • Heavy metal toxicity
  • Lead toxicity
  • Methylation
  • Neurodegeneration

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Applying epigenetics to alzheimer's disease via the latent early-life associated regulation (LEARn) model. / Maloney, Bryan; Sambamurti, Kumar; Zawia, Nasser; Lahiri, Debomoy.

In: Current Alzheimer Research, Vol. 9, No. 5, 06.2012, p. 589-599.

Research output: Contribution to journalArticle

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