Down syndrome (DS), the principal cause for intellectual disability, is also associated with hormonal, immunological, and gastrointestinal abnormalities. Muscle hypotonia (MH) and congenital heart diseases (CHD) are also frequently observed. Collagen molecules are essential components for maintaining muscle integrity and are formed by the assembly of three chains, alpha 1-3. The type VI collagen is crucial for cardiac as well as skeletal muscles. The COL 1 (VI) and 2 (VI) chains are encoded by genes located at the 21st chromosome and are expected to have higher dosage in individuals with DS. The  3 (VI) chain is encoded by the COL6A3 located at the chromosome 2. We hypothesized that apart from COL6A1 and COL6A2, COL6A3 may also have some role in the MH of subjects with DS. To find out the relevance of COL6A3 in DS associated MH and CHD, we genotyped two SNPs in COL6A3, rs2270669 and rs2270668, in individuals with DS. Subjects with DS were recruited based on the Diagnostic and Statistical Manual for Mental Disorders-IV and having trisomy of the 21st chromosome. Parents of individuals with DS and ethnically matched controls were enrolled for comparison. Informed written consent was obtained for participation. Peripheral blood was used for isolation of genomic DNA. Target genetic loci were studied by DNA sequence analysis. Data obtained was subjected to population- as well as family-based statistical analysis. rs2270668 was found to be nonpolymorphic in the studied population. rs2270669 showed significant association of the ‘C’ allele and ‘CC’ genotype with DS probands having MH (P=0.02). Computational analysis showed that rs2270669 may induce structural and functional alterations in the COL 3 (VI). Interaction of COL3 (VI) with different proteins, crucial for muscle integrity, was also noticed by computational methods. This pioneering study on COL6A3 with DS related MH thus indicates that rs2270669 ‘C’ could be considered as a risk factor for DS related MH.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

Thyroid malfunction is more common in individuals with Down syndrome (DS) than in the general population. It has been hypothesized that thyroid may influence cancer risk. Individuals with DS are at greater risk of developing leukemia than the general population, while solid tumors especially breast cancer (BC) are rare. BC patients have higher levels of circulating thyroid-stimulating hormone (TSH) and prolactin (PRL), both regulated by the thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide. This study was aimed at investigating the status of TRH functional polymorphisms in subjects with DS and BC. Unrelated families with DS probands (n=180), individuals with BC (n=99) and ethnically matched controls (n=216) were recruited. Genomic DNA isolated from peripheral blood was subjected to PCR amplification followed by DNA sequence analysis. Data obtained were analyzed by population- and family-based statistical analysis. Among 30 studied sites, only 2 (rs7645772 and rs13097335) were polymorphic. Case-control analysis showed a lack of any significant association with DS, while the rs13097335 GG and GT genotype frequency was significantly different in the BC samples. A paternal-biased transmission of the G allele was observed in female DS probands. It may be concluded that rs13097335 may have a protective role toward the development of BC.