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Alzheimer's Disease (AD) is the most common form of dementia, affecting almost 50 million of people around the world, characterized by a complex and age-related progressive pathology with projections to duplicate its incidence by the end of 2050. AD pathology has two major hallmarks, the amyloid beta (Aβ) peptides accumulation and tau hyperphosphorylation, alongside with several sub pathologies including neuroinflammation, oxidative stress, loss of neurogenesis and synaptic dysfunction. In recent years, extensive research pointed out several therapeutic targets which have shown promising effects on modifying the course of the disease in preclinical models of AD but with substantial failure when transposed to clinic trials, suggesting that modulating just an isolated feature of the pathology might not be sufficient to improve brain function and enhance cognition. In line with this, there is a growing consensus that an ideal disease modifying drug should address more than one feature of the pathology. Considering these evidence, β-secretase (BACE1), Glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE) has emerged as interesting therapeutic targets. BACE1 is the rate-limiting step in the Aβ production, GSK-3β is considered the main kinase responsible for Tau hyperphosphorylation, and AChE play an important role in modulating memory formation and learning. However, the effects underlying the modulation of these enzymes are not limited by its primarily functions, showing interesting effects in a wide range of impaired events secondary to AD pathology. In this sense, this review will summarize the involvement of BACE1, GSK-3β and AChE on synaptic function, neuroplasticity, neuroinflammation and oxidative stress. Additionally, we will present and discuss new perspectives on the modulation of these pathways on AD pathology and future directions on the development of drugs that concomitantly target these enzymes. Show less

Combining different approaches (resequencing of portions of 54 obesity candidate genes, literature mining for pig markers associated with fat deposition or related traits in 77 genes, and in silico mining of porcine expressed sequence tags and other sequences available in databases), we identified and analyzed 736 SNP within candidate genes to identify markers associated with back fat thickness (BFT) in Italian Large White sows. Animals were chosen using a selective genotyping approach according to their EBV for BFT (276 with most negative and 279 with most positive EBV) within a population of ≈ 12,000 pigs. Association analysis between the SNP and BFT has been carried out using the MAX test proposed for case-control studies. The designed assays were successful for 656 SNP: 370 were excluded (low call rate or minor allele frequency <5%), whereas the remaining 286 in 212 genes were taken for subsequent analyses, among which 64 showed a P(nominal) value <0.1. To deal with the multiple testing problem in a candidate gene approach, we applied the proportion of false positives (PFP) method. Thirty-eight SNP were significant (P(PFP) < 0.20). The most significant SNP was the IGF2 intron3-g.3072G>A polymorphism (P(nominal) < 1.0E-50). The second most significant SNP was the MC4R c.1426A>G polymorphism (P(nominal) = 8.0E-05). The third top SNP (P(nominal) = 6.2E-04) was the intronic TBC1D1 g.219G>A polymorphic site, in agreement with our previous results obtained in an independent study. The list of significant markers also included SNP in additional genes (ABHD16A, ABHD5, ACP2, ALMS1, APOA2, ATP1A2, CALR, COL14A1, CTSF, DARS, DECR1, ENPP1, ESR1, GH1, GHRL, GNMT, IKBKB, JAK3, MTTP, NFKBIA, NT5E, PLAT, PPARG, PPP2R5D, PRLR, RRAGD, RFC2, SDHD, SERPINF1, UBE2H, VCAM1, and WAT). Functional relationships between genes were obtained using the Ingenuity Pathway Analysis (IPA) Knowledge Base. The top scoring pathway included 19 genes with a P(nominal) < 0.1, 2 of which (IKBKB and NFKBIA) are involved in the hypothalamic IKKβ/NFκB program that could represent a key axis to affect fat deposition traits in pigs. These results represent a starting point to plan marker-assisted selection in Italian Large White nuclei for BFT. Because of similarities between humans and pigs, this study might also provide useful clues to investigate genetic factors affecting human obesity. Show less