However, a report from the same laboratory demonstrated that NHEJ is reduced in cortical extracts from brains of AD versus normal subjects and that DNA-PKcs level was significantly lower in the AD brain extracts [74]. Whether other DNA repair systems, especially HR, are altered in the AD brains is not known (Figure ?(Figure22). Figure 2 The potential role of the www.selleckchem.com/products/Perifosine.html amyloid beta (A??)-induced loss of DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end joining (NHEJ) or homologous recombination (HR) (or both) in the development of Alzheimer’s disease (AD). ATM, Ataxia … To explain the complexity of AD, a ‘two-hit hypothesis’ for AD development has been reported; the first hit makes neurons vulnerable and the second hit triggers the neurodegenerative process [75].

The first hit may constitute abnormalities when neurons try to re-enter the cell cycle or oxidative stress, which, if persistent, can create a pro-oxidant environment as encountered in pre-AD and AD cases. In this environment, proteins highly sensitive to redox modulation, including p53, can be compromised [76]. A number of post-mortem studies suggest an involvement of p53 in AD, and high levels of p53 in certain neurons in post-mortem samples from patients with AD have been reported (reviewed in [77]). DNA-PK activates p53 by phosphorylating the amino-terminal site [78], and p53 can induce Bax, a pro-apoptotic protein that translocates to the mitochondria and initiates the intrinsic death pathway [79]. Regulation of Bax-mediated neuronal death also reportedly involves Ku70 phosphorylation by DNA-PK [80].

In this regard, reduction in DNA-PKcs levels in AD brains does not seem to be consistent with the role of DNA-PKcs as the trigger for p53-mediated neurodegeneration (Figure ?(Figure33). Figure 3 The potential link of reduced DNA-dependent protein kinase (DNA-PK), phosphorylation status of replication protein A (RPA) and p53 to neuronal apoptosis, and genomic instability that may lead to Alzheimer’s disease AV-951 (AD). A??, amyloid beta; HR, … DNA-PK is believed to have little http://www.selleckchem.com/products/ldk378.html or no effect on p53-dependent cell-cycle arrest. In contrast, there are reports linking p53 phosphorylation by DNA-PK to cellular death machinery (reviewed in [81]). DNA-PK is also involved in regulating the activities of RNA polymerase I and II via phosphorylation (reviewed in [81]). Given these important substrates of DNA-PK that are critical players in cell death and gene transcription, it is difficult to pinpoint the exact role(s) of DNA-PKcs and its cofactor (Ku80/Ku70) in AD. Likewise, it would be simplistic to directly link reduced levels of DNA-PK subunits and consequently less proficient NHEJ in AD brains to neurodegeneration.