Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27Kip1, phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) “clinical-pathological AD” (CP-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and clinical dementia (CDR≥2, IQCODE>3.8); II) “pathological AD” (P-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE<3.2); and III) “normal aging” (N) - subjects without neuropathological AD (Braak≤II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE<3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

“…NOX2 inhibition had no effect on the Mtran phenotype (CD16/32+/TGFb+), but it repolarized microglia/macrophages towards an M2-like phenotype, as demonstrated by significant increased expression TGFb (M2-like marker). In addition, we demonstrated that gp91ds-tat treatment significantly reduced H2AX protein expression in damaged cortex, a markers of oxidative stress-induced DNA damage, 25 at 7 days post-injury. Taken together, these data demonstrate that a delayed systemic intervention starting at 24 h post-injury that targets NOX2 activity in microglia/macrophages can alter M1-/M2-like balance in favor of the anti-inflammatory and neurorestorative M2-like phenotype, and this results in reduced oxidative damage in neurons at 7 days post-injury.…”

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

“…In our data set we find lower levels of PRDX5 (–1.77 and −2.27 fold) at the PSD of NDAN versus AD which can potentially indicate decreased oxidative stress in the brains of these individuals [157]. PRDX5 can neutralize hydrogen peroxide, alkyl hydroperoxides and peroxynitrite [158, 159] and its expression is increased during oxidative stress [160].…”

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

“…Transcription of the highly GC-rich 5ʹ-UTR region of FMR1 promotes R-loop formation at that locus, and increases the propensity for R-loop formation in the CGG repeat and the size of these R-loops 127 . DNA damage triggers a DNA damage response (DDR), a series of signalling events that, if not corrected, leads to neuronal death 128,129 . Phosphorylated histone variant γH2AX, which is an important DDR signalling molecule that is involved in the recruitment of repair proteins to the site of the DNA lesion, has been detected in FXTAS inclusions 130 and in a neural cell model upon doxycycline-induced expression of expanded CGG repeat reporter RNA 131 .…”