Search

Background: Aging is often characterized by a progressive loss of cognitive abilities due to the onset of Alzheimer Disease (AD). In recent years, ‐omic sciences have allowed us to begin to shed light on its molecular pathways in order to speculate about new and attractive hypothesis on AD pathogenesis. Method: In this study, a whole transcriptome analysis and a Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) from the Abbiategrasso Brain Bank (ABB) of 6 subjects with clinical and neuropathological diagnosis of AD and 3 healthy age‐matched controls in duplicate. Clinical and neuropsychological profile were obtained through serial evaluations, made at the baseline and in the following years. According to the ABB protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring. Result: Transcriptomic results showed a greater number of differentially expressed genes (DEGs) in TC (1571) and CG (1210) and a least amount of DEGs in HI (206), PC (109) and SN (60). Furthermore, the GSEA showed a difference between the group of early affected brain areas (HI, TC) and the group of the subsequently involved areas (PC, CG, SN). Notably, in HI and TC there was a significant down‐regulation of shared DEGs primarily involved in the synaptic transmission and in the development of the central nervous system (CDK5R1, KCNC1, KCNC2, BSN), while in PC, CG and SN there was a significant down‐regulation of genes primarily involved in the proper protein folding and trafficking and inflammation (HSPA1B, HSPA1A, DNAJB1, FKBP4, CHORDC1, STIP1). Conclusion: The course of AD could follow a definite time and severity‐related pattern that arises from inflammatory processes and protein misfolding, observed in PC, CG and SN, and leads to synaptic impairment, observed in HI and TC. Therefore, we can relate neurobiological processes to clinical manifestations and outline a clearer picture of AD neuropathology and pathogenesis. This could help to discover novel biological targets in order to develop effective and well‐timed therapeutical approaches. [ABSTRACT FROM AUTHOR]

Background: Aging is often characterized by a progressive loss of cognitive abilities due to the onset of Alzheimer Disease (AD). In recent years, ‐omic sciences have allowed us to begin to shed light on its molecular pathways in order to speculate about new and attractive hypothesis on AD pathogenesis. Method: In this study, a whole transcriptome analysis and a Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) from the Abbiategrasso Brain Bank (ABB) of 6 subjects with clinical and neuropathological diagnosis of AD and 3 healthy age‐matched controls in duplicate. Clinical and neuropsychological profile were obtained through serial evaluations, made at the baseline and in the following years. According to the ABB protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring. Result: Transcriptomic results showed a greater number of differentially expressed genes (DEGs) in TC (1571) and CG (1210) and a least amount of DEGs in HI (206), PC (109) and SN (60). Furthermore, the GSEA showed a difference between the group of early affected brain areas (HI, TC) and the group of the subsequently involved areas (PC, CG, SN). Notably, in HI and TC there was a significant down‐regulation of shared DEGs primarily involved in the synaptic transmission and in the development of the central nervous system (CDK5R1, KCNC1, KCNC2, BSN), while in PC, CG and SN there was a significant down‐regulation of genes primarily involved in the proper protein folding and trafficking and inflammation (HSPA1B, HSPA1A, DNAJB1, FKBP4, CHORDC1, STIP1). Conclusion: The course of AD could follow a definite time and severity‐related pattern that arises from inflammatory processes and protein misfolding, observed in PC, CG and SN, and leads to synaptic impairment, observed in HI and TC. Therefore, we can relate neurobiological processes to clinical manifestations and outline a clearer picture of AD neuropathology and pathogenesis. This could help to discover novel biological targets in order to develop effective and well‐timed therapeutical approaches. [ABSTRACT FROM AUTHOR]