PSEN1 blocking peptide

Background Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic A beta peptides. Amongst these, A beta(1-43)is more prone to aggregation and has higher toxic properties than the long-known A beta(1-42). However, a direct effect on A beta(1-43)in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods N = 1431 AD patients (n = 280 early-onset (EO) andn = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened forAPPandPSENs. For the first time, A beta(1-43)levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the commonPSEN1p.E318G variant and compared with A beta(1-42)and A beta 1-40CSF levels. The soluble sAPP alpha and sAPP beta species were also measured for the first time in mutation carriers. Results A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6%PSEN1, 1.07%APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF A beta(1-43)levels compared to controls (p = 0.037; < 0.001). CSF A beta(1-43)levels positively correlated with CSF A beta(1-42)in both pathogenic and unclear carriers and controls (allp < 0.001). The p.E318G carriers showed reduced A beta(1-43)levels (p < 0.001), though genetic association with AD was not detected. sAPP alpha and sAPP beta CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using A beta(1-43)and A beta(1-42)levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations. Conclusion This is the first time that A beta(1-43)levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of A beta(1-43)inAPPandPSENscarriers highlights the pathogenic role of longer A beta peptides in AD pathogenesis. Alterations in A beta(1-43)could prove useful in understanding the pathogenicity of unclearAPPandPSENsvariants, a critical step towards a more efficient genetic counselling.

Amyloid-beta (A beta) cleaved from amyloid precursor protein (APP) has been proposed to play a central and causative role in the aetiology of Alzheimer's disease (AD). APP(swe)/PSEN1(dE9) (APP/PS1) transgenic mice display chronic A beta accumulation and deposition in the brain. L-arginine is a semi-essential amino acid with a number of bioactive metabolites, and altered arginine metabolism has been implicated in the pathogenesis and/or the development of AD. This study systematically investigated how arginine metabolic profiles changed in the frontal cortex, hippocampus, parahippocampal region and cerebellum of male APP/PS1 mice at 4, 9 and 17 months of age relative to their sex- and age-matched wildtype controls. Immunohistochemistry demonstrated age-related A beta deposition in the brain. High-performance liquid chromatography and mass spectrometry revealed age-related increases in glutamine, spermidine and spermine in APP/PS1 mice in a region-specific manner. Notably, genotype-related increases in spermine were found in the frontal cortex at the 9-month age point and in the frontal cortex, hippocampus and parahippocampal region at 17 months of age. Given the existing literature indicating the role of polyamines (spermine in particular) in modulating the aggregation and toxicity of A beta oligomers, increased spermidine and spermine levels in APP/PS1 mice may be a neuroprotective mechanism to combat A beta toxicity. Future research is required to better understand the functional significance of these changes.