NEW YORK (GenomeWeb) – New research is suggesting that Alzheimer's disease (AD) tends to coincide with certain chromatin shifts in the aging brain.
Researchers from the University of Pennsylvania used chromatin immunoprecipitation sequencing to profile genome-wide patterns for the age-related chromatin histone acetylation mark H4K16ac in brain samples from a dozen individuals with AD, as well as unaffected individuals across the age spectrum. In contrast to aged brain samples from cognitively normal controls, which were enhanced for H4K16ac, they saw lower-than-usual H4K16ac levels.
As reported online today in Nature Neuroscience, the team's functional analysis pointed to at least three main H4K16ac patterns in AD-affected brains: those overlapping with normal brain aging, dysregulation at age-related pathways, and disease-specific H4K16ac losses and gains.
"Our study proposes a mechanism to explain how age is a risk factors for AD: a particular histone modification, whose accumulation is strongly associated with aging, is dysregulated in AD," senior authors Shelley Berger, Nancy Bonini, and Brad Johnson, all at the University of Pennsylvania, said in a statement. "These findings and their replication in future work using patients from other biobanks open the possibility that prevention of age-dysregulation at the chromatin level may be a therapeutic avenue for AD."
Using the Illumina NextSeq 500 instrument, the researchers did ChIP-seq targeting H4K16ac in post-mortem samples from the lateral temporal lobes of the brains of 12 individuals with AD who had a mean age of 68 years old. They did similar ChIP-seq-based profiling on samples from 10 older individuals with a mean age of 68 years old and nine somewhat younger individuals with a mean age of 52 years old.
"[W]e considered that epigenetic regulation by H4K16ac may be involved in aging of the human brain and perhaps in the progression of AD," the authors wrote.
In the AD-affected brain samples, the team detected roughly 323,000 H4K16ac peaks by ChIP-seq — slightly fewer than the 349,000 or so peaks in the brain samples from older, unaffected individuals. Consistent with the histone mark's ties to aging, the young brain samples had just 239,000 H4K16ac peaks.
When they dug into the H4K16ac mark distribution and overlap between the three groups, the researchers saw more pronounced overlap between the brain samples from older, healthy individuals and the AD sufferers. Around 183,000 H4K16ac peaks overlapped between those groups compared to a 153,000-peak overlap between samples from old and young controls and a 146,000-peak overlap in young controls and AD cases. Even so, the peaks were largely distinct in the younger, older, and AD groups.
The team folded in genome-wide H4K16ac profiles from mouse samples and human fibroblast cells for subsequent analyses delving into the H4K16ac dynamics — the H4K16ac peaks lost or gained in the younger, aging, and AD-affected individuals. Again, the results pointed to epigenetic dysregulation in the lateral temporal lobe in AD, rather than enhanced adoption of age-related H4K16ac histone acetylation marks, with many marks moving in opposite directions in AD-affected and healthy aging brains.
"[T]he negative correlation between aging and disease clarifies an important question in the field, that is, whether AD is a simple exacerbation of aging or rather a dysregulation of aging," the authors explained. "Our results reveal the more complex latter scenario, where there is a clear component of dysregulation of aging in the pathology of AD."