Abstract
Alzheimer’s Disease (AD) is a major health problem worldwide. The lack of efficacy of existing therapies for AD is because of diagnosis at late stages of the disease, limited knowledge of biomarkers, and molecular mechanisms of AD pathology, as well as conventional drugs that are focused on symptomatic rather than mechanistic features of the disease. The connection between epigenetics and AD, however, may be useful for the development of novel therapeutics or diagnostic biomarkers for AD. The aim of this study was to investigate a pathogenic role for epigenetics and other biomarkers in the male APP/BIN1/COPS5 triple-transgenic (3xTg) mouse model of AD. In the APP/BIN1/COPS5 3xTg-AD mouse hippocampus, sirtuin expression and activity decreased, HDAC3 expression and activity increased, PSEN1 mRNA levels were unchanged, PSEN2 and APOE expression was reduced, and levels of the pro-inflammatory marker IL-6 increased; levels of pro-inflammatory COX-2 and TNFα and apoptotic (NOS3) markers increased slightly, but these were non-significant. In fixed mouse-brain slices, immunoreactivity for CD11b and β-amyloid immunostaining increased. APP/BIN1/COPS5 3xTg-AD mice are a suitable model for evaluating epigenetic changes in AD, the discovery of new epigenetic-related biomarkers for AD diagnosis, and new epidrugs for the treatment of this neurodegenerative disease.
Highlights
Neurodegenerative disorders (NDDs) are major public health problems and are usually linked to ageing
Since neuroepigenetics may play an important role in neurodegenerative processes, the current study investigated whether the amyloid precursor protein (APP)/bridging integrator 1 (BIN1)/constitutive photomorphogenic homolog subunit 5 (COPS5) 3xTg-Alzheimer’s disease (AD) mouse model is a good tool for studying epigenetic contributions to AD
These data revealed that APP/BIN1/COPS5 3xTg-AD mice exhibit an extensive pattern of neuroinflammation that correlated with acute neurodegenerative pathologies, highlighted by increased Aβ deposition, substantial neuroinflammation, and cell death in the neocortex and hippocampus
Summary
Neurodegenerative disorders (NDDs) are major public health problems and are usually linked to ageing. Alzheimer’s disease (AD) is the leading cause of dementia (>50%), affecting 45–50 million individuals worldwide [1]; over 58% of these patients live in lowand middle-income countries [2]. AD affects an estimated 6.2 million Americans aged 65 years and older. According to official death records, AD was the sixth-leading cause of death in the United States in 2019, and the fifth-leading cause of death among Americans 65 years and older. Fatalities from stroke, heart disease, and HIV declined between 2000 and 2019; recorded deaths from AD increased by more than 145% during this same period [5]. This increased trajectory in the number of AD-related fatalities was likely exacerbated in 2020 by the COVID-19 pandemic [5]. New biomarkers that allow the early diagnosis and treatment of AD are, required
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