Biology subjects

Gutta, G.

Publications and source records attributed to Gutta, G..

2 recordsLinked to original sources

bioRxiv2025

The interaction between aging and DNA damage influences the accumulation of APP in Alzheimer's disease

DNA damage is a major driver of the aging process, and the progression of Alzheimers disease (AD) worsens the situation. Neurons of the AD brain show significantly elevated levels of DNA damage compared to controls. AD is also associated with altered processing of the amyloid precursor protein (APP), best known for its A{beta} proteolytic peptide fragment. In the current work we find that these three elements - age, DNA damage, and APP - are associated with each other. We present evidence from the mouse brain supporting the hypothesis that DNA damage drives increased levels of APP. Using the TUNEL reaction to track DNA damage, we show that TUNEL staining increases significantly with age (6 months to 24 months, 8 females and 14 males total in this study), in lockstep with intracellular APP. To separate correlation from causality we analyzed tissue from mice genetically deficient in ATM (ataxia-telangiectasia mutated), a protein kinase that promotes DNA damage repair. Compared to 6-month wild type mice, the increased TUNEL signal in neurons of 6-month Atm-/- animals was equivalent to that seen in 24-month wild type. Significantly, the APP signal in the Atm-/- cells was also increased, and this correlation was found in both neuronal and non-neuronal cells. These results suggest that the loss of genomic integrity associated with aging is a cellular stressor that increases the levels of APP and thus increases vulnerability to the pathogenesis of AD. SIGNIFICANCE STATEMENTOur work links the genetics of Alzheimers disease (dominant disease-causing mutations in the APP gene) with DNA damage and aging - two factors known as risk factors in AD. The evidence suggests that the enhanced DNA damage associated with the normal aging process, increases the levels of APP thus potentially contributing to A{beta} production and plaque formation.

neuroscience↗

bioRxiv2024

DNA damage and senescence in the aging and Alzheimer's disease cortex are not uniformly distributed

Alzheimers disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age-dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. The connection between aging and the loss of genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells has been reported to increase with age, and their senescence-associated secreted products are likely contributing factors to age-related illnesses. We tracked DNA damage with 53BP1 and cellular senescence with p16 immunostaining of human post-mortem brain samples. We found that DNA damage is significantly increased in the BA9 region of the AD cortex when compared to the same region of unaXected controls (UC). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell-by-cell basis, we found that the intensity of the two markers was tightly linked in the AD, but not the UC brain. To test whether DNA damage was a causal factor in the emergence of the senescence program, we used etoposide treatment to damage the DNA of cultured mouse primary neurons. While DNA damage increased after treatment, after 24 hours no change in the expression of senescence-associated markers was observed. Our work suggests that DNA damage and cellular senescence are both increased in the AD brain and increasingly coupled. We propose that in vivo the relationship between the two age-related processes is more complex than previously thought.

neuroscience↗