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A significant number of individuals with type 2 diabetes (T2DM) develop cognitive deficits over time that in some cases could lead to dementia. It remains to be identified the diabetes-related factors or comorbid conditions that drive the association and how they work. In this manuscript, we show that 14-15 month-old hAPP NL/F mice, a knock‐in mouse model of preclinical Alzheimer’s disease (AD) (that is, they generate Aβ42 at an early age but do not show symptoms of the disease until they are old), but not wild type, develop behavioural deficits that correlate with electrophysiological and dendritic spine changes when affected by T2DM. The deficits are not paralleled by higher levels of toxic forms of amyloid beta-peptide (Aβ ) or by neuroinflammation but by a reduction in γ -secretase activity, in turn accountable, among other consequences, for a reduction in the levels of the synaptogenesis regulator protein PSD95, and by increased phosphorylation of Tau at epitopes of dendritic spine targeting. RNAseq analysis of the cerebral cortex of wild type and hAPP NL/F, with and without T2DM, revealed the significant downregulation of hypoxia inducible factor 3 (HIF-3α) in the hAPP NL/F diabetic mice only, a decrease that was also observed at the protein level. The main conclusion of this work is that T2DM will trigger or accelerate cognitive illness fundamentally in those individuals who already have a genetic predisposition to AD. A second conclusion is that the cognitive disorders produced by diabetes in these individuals are not due to the excess of toxic forms of Aβ but to other causes, including loss of function of γ -secretase. The third conclusion is that an alteration of the response to hypoxia through Hif3α would be mediating the negative effects of T2DM in the brain.

In this work, we tested the hypothesis that the development of dementia in individuals with type 2 diabetes (T2DM) requires a genetic background of predisposition to neurodegenerative disease. As a proof of concept, we induced T2DM in middle-aged hAPP NL/F mice, a preclinical model of Alzheimer’s disease. We show that T2DM produces more severe behavioral, electrophysiological, and structural alterations in these mice compared with wild-type mice. Mechanistically, the deficits are not paralleled by higher levels of toxic forms of Aβ or by neuroinflammation but by a reduction in γ-secretase activity, lower levels of synaptic proteins, and by increased phosphorylation of tau. RNA-seq analysis of the cerebral cortex of hAPP NL/F and wild-type mice suggests that the former could be more susceptible to T2DM because of defects in trans-membrane transport. The results of this work, on the one hand, confirm the importance of the genetic background in the severity of the cognitive disorders in individuals with T2DM and, on the other hand, suggest, among the involved mechanisms, the inhibition of γ-secretase activity.

Sleep homeostasis occurs during prolonged wakefulness. Drowsiness and sleep pressure are its behavioral manifestations and, when sleep is allowed, there is a sleep rebound of sufficient duration and intensity to compensate for the previous deprivation. Adenosine is one of the molecules involved in sleep homeostasic regulation. Caffeine and theophylline, stimulants widely consumed by the humans, are antagonists. It is an endogenous factor, resulting from ATP metabolism in neurons and glia. Adenosine accumulates in the extracellular space, where it can exert regulatory actions on the sleep-wakefulness cycle circuits. Adenosine acts through the purinergic receptors A1 and A2. This paper reviews: 1) the metabolic pathways of cerebral adenosine, and the mechanisms of its release by neurons and glia to the extracellular space; 2) the actions of adenosine and its antagonists in regions of the central nervous system related to wakefulness, non-REM sleep, and REM sleep, and 3) the synaptic mechanisms involved in these actions.

La homeostasis del sueño se manifiesta ante situaciones de vigilia prolongada de forma natural o experimentalmente. En estos casos, se presenta somnolencia (o presión de sueño) y, cuando se permite dormir, hay un rebote del sueño en duración e intensidad que compensa la pérdida del mismo. Entre las moléculas que pueden intervenir en la regulación homeostática del sueño, se encuentra la adenosina, cuyos antagonistas, la cafeína y la teofilina, consume la población humana ampliamente como estimulantes. La adenosina es un factor endógeno resultante del metabolismo del ATP en neuronas y glía que se acumula en el medio extracelular y que es capaz de ejercer acciones reguladoras sobre circuitos del ciclo vigilia sueño. Actúa a través de los receptores purinérgicos A1 y A2. En este trabajo se presenta una revisión de las vías metabólicas de la adenosina cerebral y de su liberación por neuronas y glía, y se exponen las acciones de la adenosina y de sus antagonistas en regiones del sistema nervioso central de naturaleza hipnogénica y relacionadas con la vigilia. Se exponen, además, los mecanismos sinápticos involucrados en estas acciones, Ayuda FPU2009-06991 del Ministerio de Ciencia e Innovación. M.C.C. tiene una beca de iniciación de estudios de posgrado concedida por la Universidad Autónoma de Madrid.