Rescue of Early bace-1 and Global DNA Demethylation by S-Adenosylmethionine Reduces Amyloid Pathology and Improves Cognition in an Alzheimer's Model.
General DNA hypomethylation is associated with Alzheimer's disease (AD), but it is unclear when DNA hypomethylation starts or plays a role in AD pathology or whether DNA re-methylation would rescue early amyloid-related cognitive impairments. In an APP transgenic mouse model of AD-like amyloid pathology we found that early intraneuronal amyloid beta build-up is sufficient to unleash a global and beta-site amyloid precursor protein cleaving enzyme 1 (bace-1) DNA demethylation in AD-vulnerable brain regions. S-adenosylmethionine administration at these early stages abolished this hypomethylation, diminished the amyloid pathology and restored cognitive capabilities. To assess a possible human significance of findings, we examined the methylation at 12 CpGs sites in the bace-1 promoter, using genome-wide DNA methylation data from 740 postmortem human brains. Thus, we found significant associations of bace-1 promoter methylation with β-amyloid load among persons with AD dementia, and PHFtau tangle density. Our results support a plausible causal role for the earliest amyloid beta accumulation to provoke DNA hypomethylation, influencing AD pathological outcomes.
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Sonia
S
Do Carmo
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Cecilia E
CE
Hanzel
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Marie L
ML
Jacobs
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Ziv
Z
Machnes
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
M Florencia
MF
Iulita
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.|Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Jingyun
J
Yang
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.|Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Lei
L
Yu
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Adriana
A
Ducatenzeiler
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Marc
M
Danik
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Lionel S
LS
Breuillaud
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.|Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
David A
DA
Bennett
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Moshe
M
Szyf
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
A Claudio
AC
Cuello
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