Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD.
A very low-density lipoprotein (HDL) mimetic peptide 4F was shown to alleviate AD-related deficits in APP transgenic mice, and this editorial highlights a study by Chernick et al. who use both mouse and human neuroglial cells to explore the mechanism underlying beneficial effects of this peptide.
Moreover, PLD3 mRNA expression inversely correlates with hippocampal β-amyloid burden, which adds evidence to the hypothesis that PLD3 protein may contribute to AD development by modifying APP processing.
We constructed the family pedigree, evaluated mutations usually associated with early-onset Alzheimer's disease (APP, PSEN1, PSEN2), and assessed polymorphisms in the apolipoprotein E (APOE) gene and in cytokine genes that we had previously found to be associated with a higher risk of LOAD (IL-10, IL-6, TNF-α).
Protective Effect of Notoginsenoside R1 on an APP/PS1 Mouse Model of Alzheimer's Disease by Up-Regulating Insulin Degrading Enzyme and Inhibiting Aβ Accumulation.
A coding gene variant rs63750847" genes_norm="351">A673T (rs63750847) in the APP gene has recently been recognized as a protective variant of late-onset Alzheimer's Disease in a large Icelandic population and has been observed recurrently in populations from Nordic countries.
Identification of the key molecules involved in chronic copper exposure-aggravated memory impairment in transgenic mice of Alzheimer's disease using proteomic analysis.
Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing.
Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease-like symptoms.
Importantly, mutations in the genes of APP and the two homologous PS proteins are a major cause of familial early onset AD, indicating that the metabolism of APP and generation of Aβ play critical roles in the initiation of the disease.
Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.