Regulation of gene expression by the APP family in the adult cerebral cortex

Abstract

Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. APP has two homologs, amyloid precursor-like protein 1 and 2 (APLP1 and APLP2), and they have functional redundancy. APP intracellular c-terminal domain (AICD), produced by sequential α- or β- and γ-secretase cleavages, is thought to control gene expression, similarly as the ICD of Notch. To investigate the role of APP family in transcriptional regulation, we examined gene expression changes in the cerebral cortex of APP/APLP1/APLP2 conditional triple knockout (cTKO) mice, in which APP family members are selectively inactivated in excitatory neurons of the postnatal forebrain. Of the 12 previously reported AICD target genes, only Nep and Npas4 mRNA levels were significantly reduced in the cerebral cortex of cTKO mice, compared to littermate controls. We further examined global transcriptional changes by RNA-seq and identified 189 and 274 differentially expressed genes in the neocortex and hippocampus, respectively, of cTKO mice relative to controls. Gene Ontology analysis indicated that these genes are involved in a variety of cellular functions, including extracellular organization, learning and memory, and ion channels. Thus, inactivation of APP family alters transcriptional profiles of the cerebral cortex and affects wide-ranging molecular pathways.

Revealing genetic links of Type 2 diabetes that lead to the development of Alzheimer’s disease

“…Table 3 shows Metagene 9 is involved in hsa04974:protein digestion and absorption as the most significant (p-value <0.05) KEGG pathway. In a recent study, protein digestion and absorption pathway was reported as one of the most significant pathway was in diabetic complications in the adult neocortex [ 77 ]. Table 3 further lists the significant enrichments of Metagene 9 reported GO terms in biological processes (BP) is in brain development (GO:0007420) [ 78 , 79 ].…”

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

“…The two APP homologues APLP1 and APLP2 are similarly processed by the same secretases, producing the intracellular fragments APLP-Intracellular Domain 1 (ALID1) and ALID2, respectively [ 52 ]. Similarly to AICD, ALID1 and ALID2 have been proposed to play a functional role as transcriptional regulators [ 53 ], although the validity of these speculations is still controversial due to the lack of adequate animal models.…”

Comparative binding analysis of WGX50 and Alpha-M with APP family proteins APLP1 and APLP2 using structural-dynamics and free energy calculation approaches

“…These findings highlight the importance of the close association of working among all three proteins under healthy conditions. 26 In treating complex diseases like A.D., one major challenge is the lack of defined objective diagnostic criteria and robust biological markers of A.D. 27 Other issues are the failure of drugs due to their adverse side effects. For example, Gantenerumab causes micro hemorrhage; Gamma Gard causes headache and nausea, Scyllo-inositol causes depression, etc.…”

“…These findings highlight the importance of the close association of working among all three proteins under healthy conditions. 26…”