Unraveling the transcriptome of pyramidal neurons from human hippocampus under aging, amnestic mild-cognitive impairment, and sex-interactions

Aim: Amnestic mild cognitive impairment (aMCI) is a transitional stage toward Alzheimer’s disease (AD). For late-onset AD (95% of cases), aging is the main risk factor. Systematizing the transcriptome of hippocampal neurons under the native conditions of this disease is essential, as this information is scarce and the hippocampus is a highly vulnerable cerebral region. Methods: Public microarray data corresponding to homogenates of human hippocampus of Healthy-Younger, Healthy-Elder, and Elder-with-MCI individuals were re-analyzed herein. Through an optimized computational pipeline, those genes having splice forms and that belong to the neuronal type were identified. The differential genes arising from each group were then characterized by contrasting ontologies (functions, cellular components, and pathways). Additionally, the data were re-arranged factorially to determine the first- and second-order sex interactions. Results: Around 76% of the relevant changes actually occurred during the healthy-aging process, being further balanced or not during MCI. “Cognition”, “behavior”, “glutamatergic synaptic transmission”, “lipid rafts”, and “catecholamines” decreased across the three groups analyzed, whereas “associative/visual learning”, “gliogenesis”, “neuro-inflammation”, “corticosteroids”, “p75NTR”, “ER-stress” and “autophagy” peaked in Elders. On the contrary, “Learning/memory”, “GAP junctions”, “GABAergic transmission”, and “GNDF” showed a minimum in Elders. The “transcriptional regulators” (MeCP2, NPAS4, DREAM), “BNDF/NGFR”, “Ca2+ transport”, “CRHR1” and “CXCL12” were minimal in MCI. From Elder to MCI, “MAPKs”, “MEF2C”, “RGS7”, “CCKBR1”, “ErbB4”, “ERK5”, and “Ca2+-Na+-K+ channels” (RYR2, SCNA1/A8, KCNQ2/Q3, KCNN3, KCNIP2) appeared downregulated. “Long-term synaptic depression” (LTD) increased sharply in the MCI. Most of the findings detected were contrasted against 250 reports. Conclusions: The multiple alterations in the basic mechanisms—mainly in the CA3 dendrites of mossy fibers could be compatible with neuronal hyper-excitability, diminished synaptic transmission, and changes in the theta/gamma/SWR rhythms. Many functionalities appeared conditioned by sex-interactions. Particularly, women showed “pure” sex-effects and interactions with “cross-over” effects. Due to its consequences on the higher-order functions, all these predictions should be confirmed experimentally.