Alzheimer's disease: the quest to understand complexity.
Alzheimer's disease (AD) is a complex disorder of the central nervous system that affects an increasing number of people worldwide due to the overall aging of the human population. In addition to genetics, which accounts for a small fraction of all cases, the etiology is multifactorial with other currently unknown triggers. It is crucial to unravel the physiological mechanisms that, being disrupted, could lead to neurodegeneration, as this knowledge could ultimately lead to the identification of novel neuroprotective strategies that could be used as therapeutics. Although mitochondrial dysfunction and the resultant oxidative stress are believed to play a major role in the pathogenesis of both early- and late-onset AD, it is conceivable that the altered physiological state of the cells leading to sporadic AD could involve additional mechanisms. Much evidence suggests that epigenetic modification of gene expression can accumulate with age leading to an altered response to stress and to an enhanced susceptibility to diseases. Since aging has a major impact in different late-onset, complex diseases and, in particular, in the late-onset forms of AD, epigenetic alterations might play an important role in the pathophysiology of this disorder. Studies exploring this idea are underway and suggest that both methylation abnormalities in AD-related genes due to disruption of mechanisms that regulate the availability of methyl groups (SAM/HCY cycle) and changes of global histone acetylation levels might play a role in neurodegeneration. Thus, it is essential to undertake novel global approaches, which may lead to the development of new avenues for therapeutic intervention.
Marques
Sueli C F
SC
Programa Doutoral em Biologia Experimental e Biomedicina, Centro de Neurociências e Biologia Celular, Coimbra, Portugal.
Oliveira
Catarina R
CR
Outeiro
Tiago F
TF
Pereira
Claudia M F
CM
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology