The pathological presentation of AD, the leading www.selleckchem.com/products/MDV3100.html cause of senile dementia, involves regionalized neuronal death and an accumulation of neuronal and extracellular lesions termed neurofibrillary tangles and senile plaques, respectively (reviewed in [6]). Several independent hypotheses have been proposed to link the pathological lesions and neuronal cytopathology with, among others, apolipoprotein E genotype [7,8], hyperphosphorylation of cytoskeletal proteins (neurofilaments and Tau) [9], and amyloid-?? metabolism [10]. However, not one of these theories alone is sufficient to explain the diversity of biochemical and pathological abnormalities of AD. There is limited evidence for neuronal loss in most amyloid precursor protein (APP) models, and when neuronal loss was noted, it was modest [11-13].

Cellular damage by oxidative stress has been proposed as a causative factor in pathophysiology of AD and normal aging. Elevated levels of oxidative damage in both nuclear DNA and mitochondrial DNA have been reported in brains of patients with AD [14], and BER deficiency has been found in post-mortem brains of sporadic patients with AD [15]. However, impaired BER activity found in neuropathological brain regions and in the cerebellum where there is no neuronal death indicates that BER deficiency is not specific to human AD brains [16]. The lack of a difference in BER activity between wild-type and AD model mice brains in any age group [17] indicates that species-specific mechanisms may be involved in AD progression.

Nonetheless, progressive neuronal loss due to cumulative damage to DNA and lack of DNA repair has been hypothesized to contribute to AD and stroke [18,19]. Moreover, human hereditary syndromes with genetic defects in the DNA repair process manifest in early-onset developmental and progressive neurodegeneration, indicating that defects in DNA damage repair are neuropathological [20,21]. In the four major DNA repair pathways (double-strand DNA (dsDNA) break repair (HR and NHEJ), NER, BER, and mismatch repair), key proteins, including some with dual functions, participate in DNA damage sensing/repair and apoptosis (Table ?(Table1)1) [16]. The focus of this review is on how DNA-PK activity may be linked to AD and whether a ’cause and effect’ scenario Brefeldin_A emerges from the reported studies. Table 1 Key proteins involved in various types of DNA repair DNA-dependent protein kinase, a multi-subunit enzyme DNA-PK is a PI3 kinase family member, and like targets of other members (ATR and ATM) of this most family, its preferential targets of phosphorylation are the serines and threonines followed by a glutamine (S-T/Q sites), although other S-T/hydrophobic residues are also phosphorylated [22]. DNA-PK enzyme activity is essential for NHEJ [5].