PMC:4034082 / 41998-46095 JSONTXT

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Gene Interactions\nAlthough APP and PSEN mutations are considered causative factors for AD, the total number of mutations identified in the APP, PSEN1 and PSEN2 genes account for less than 3% of the cases with AD, clearly indicating that neurodegeneration associated with AD pathogenesis cannot be exclusively attributed to APP/PSEN-related cascades (amyloid hypothesis). Alterations in the ubiquitin-proteasome system and biochemical disarray in the chaperone machinery are alternative and/or complementary pathogenic events potentially leading to defects in protein synthesis, folding, and degradation with subsequent conformational changes, aggregation, and accumulation in cytotoxic deposits [8,11]. A more plausible explanation would seem to be that multiple susceptibility SNPs with a very subtle genetic variation cooperatively contribute, in concert with environmental factors and concomitant CNS vulnerability, to premature neurodegeneration in dementia. \nWe have compared the distribution and frequency of major polymorphic variants of different genes potentially associated with AD (i.e., APOE, PSEN1, A2M-V1001, A2M-I/D, ACE, FOS, AGT-235, AGT-174, eNOS3-E298D, eNOS3-27bpTR, CETP, MTHRF) in the general population, in adults (\u003e45 years) with no family history of dementia, and in patients with dementia, and could not find any significant differences among the three groups except in the case of the APOE gene, which exhibits a clear accumulation of APOE-3/4 and APOE-4/4 genotypes (overload of the APOE-4 allele) in AD cases [7]. If we consider that a genetic variation higher than 2% could be of significant value, then several polymorphisms clearly differ in AD as compared with the other two population clusters, including the PSEN1-1/2, ACE-D/D, ACE-I/I, CEPT-B1/B1, and MTHFR-T/T polymorphisms [7]. \nDefective functions of genes associated with longevity may influence premature neuronal survival, since neurons are potential pacemakers defining life span in mammals [8,16]. Hypothalamic expression of CREB-binding protein (CBP) and CBP-binding partner Special AT-rich sequence binding protein 1 (SATB-1) is highly correlated with lifespan across five strains of mice, and expression of these genes decreases with age and diabetes in mice. In a transgenic Aβ42 model of AD, cbp-1 RNAi prevents protective effects of bacterial dilution (bDR) and accelerates Aβ42-related pathology. Consistent with the function of CBP as a histone acetyltransferase, drugs that enhance histone acetylation increase lifespan and reduce Aβ42-related pathology, protective effects completely blocked by cbp-1 RNAi. Other factors implicated in lifespan extension are also CBP-binding partners, suggesting that CBP constitutes a common factor in the modulation of lifespan and disease burden by DR and the insulin/IGF1 signaling pathway [92].\nAD patients have been reported to have shorter telomeres in peripheral blood leukocytes (PBLs) than age-matched control subjects. However, it is unclear if PBL telomere length reflects brain telomere length, which might play a more direct role in AD pathogenesis. Lukens et al. [93] examined the correlation between PBL and cerebellum telomere length in AD patients.The PBL and cerebellum telomere lengths were directly correlated in individuals with AD. Nonetheless, cerebellum telomere lengths were not significantly different in AD patients and age-matched control subjects. Reduced PBL telomere length in AD might not reflect reduced telomere length in bulk brain tissue, but may be a marker of changes in a subset of brain tissues or other tissues that affect the pathogenesis of AD. Zekry et al. [94] evaluated the usefulness of telomere length alone or combined with APOE polymorphism in diagnosing mild cognitive impairment (MCI) and in differentiating AD from vascular and mixed dementia. Although APOE-4 was associated with dementia, no significant differences in telomere length were found among patients with different types of dementia. The combination of telomere length and APOE-4 did not confer a significantly higher dementia risk [94].\n"}