Meningeal γδ T cells are biased toward IL-17 production and control hippocampal synaptic plasticity and short-term memory.

Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A_2A receptor (A_2AR), which is upregulated in the human forebrain of aged and Alzheimer’s disease (AD) patients. We have previously shown that an anti-A_2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A_2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A_2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A_2AR over-activation and were rescued by anti-A_2AR therapy; finally, we demonstrate that A_2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A_2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A_2AR antagonists, namely caffeine, on Alzheimer’s and age-related cognitive impairments may rely on its ability to modulate GR actions.

Alpha-synuclein (aSyn) is assumed to be a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson’s disease and, one common molecular alteration among these disorders is an age-associated increase in protein glycation. Thus, we hypothesized that glycation-induced dysfunction of neuronal pathways might be an underlying molecular cause of synucleinopathies. Here, we evaluated if increased brain glycation modulated motor and/or non-motor phenotypes in a mouse model of synucleinopathies. In addition, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain, and unveiled the major molecular pathways altered. Age-matched (16 weeks old) male aSyn transgenic (Thy1-aSyn) or WT mice received a single dose of MGO or vehicle via intracerebroventricular (ICV) injection. Behavioural phenotypes were analysed 4 weeks post-treatment, and, at the end of the tests, biochemical and histological studies were conducted on brain tissue. We found that glycation potentiates motor dysfunction, assessed by vertical pole, rotarod and hindlimb clasping tests in Thy1-aSyn mice. In addition, it induces cognitive impairment (Y maze test), olfactory disturbances (block test), and colonic dysfunction. These behavioural changes were accompanied by the accumulation of aSyn in the midbrain, striatum, and prefrontal cortex, and by an overall increase in glycation in the midbrain and cerebellum. Furthermore, MGO induced neuronal and dopaminergic cell loss in the midbrain of Thy1-aSyn mice. Quantitative proteomic analysis revealed that, in Thy1-aSyn mice, MGO mainly impacts on glutamatergic proteins in the midbrain, but not in the prefrontal cortex, where it mainly affects the electron transport chain. Among the altered proteins in the midbrain, we found an upregulation of N-Methyl- _D -Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors levels, glutaminase, vesicle glutamate transporter (VGLUT), and the excitatory amino acid transporter (EAAT1), suggesting potentiation of glutamatergic signalling. Overall, we demonstrated that MGO-induced glycation accelerates Parkinsonian-like sensorimotor and cognitive alterations. The increase in glutamatergic-related proteins in the midbrain may represent a compensatory mechanism to the MGO-induced dopaminergic neurodegeneration. Our study sheds light into the enhanced vulnerability of the midbrain in Parkinson’s disease-related synaptic dysfunction that, ultimately leads to cell loss, and provides molecular insight into the observation that glycation suppressors and anti-glutamatergic drugs hold promise as disease-modifying therapies for synucleinopathies.

N-methyl-D-aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A and/or GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch-clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B-NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic derived C-terminal fragments, rather than APP full length, contribute to aberrant GluN2B-NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain, and interfering with this mechanism normalized the aberrant currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments. In brief Rajão-Saraiva et al. identified the APP full-length protein as a regulator of glutamatergic transmission in immature synapses, by controlling GluN2B synaptic content and mediated currents during postnatal development. Upon aging, the APP amyloidogenic derived C-terminal fragments, rather than APP full length, contribute to aberrant GluN2B-NMDAR currents. Our work highlights the importance of keeping APP processing under tight control, to ensure the normal functioning of glutamatergic synapses, being particularly relevant to understand age-related synaptic impairments and AD.