Plasma Neurodegenerative Biomarkers in Cognitively Preserved Nonagenarians.

Plasma biomarkers represent promising tools for the screening and diagnosis of patients with neurodegenerative conditions. However, it is crucial to account for the effects of aging on biomarker profiles, especially in the oldest segments of the population. Additionally, biomarkers in this sample can offer in vivo insights into the physiological mechanisms underlying brain aging while concomitantly supporting cognitive preservation.

Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration.

Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is unexplored. We found that the activation of astrocyte mitochondrial-associated type-1 cannabinoid (mtCB) receptors determines MERC-dependent intracellular calcium signaling and synaptic integration.

Cannabinoid-induced motor dysfunction autophagy inhibition.

The recreational and medical use of cannabis is largely increasing worldwide. Cannabis use, however, can cause adverse side effects, so conducting innovative studies aimed to understand and potentially reduce cannabis-evoked harms is important. Previous research conducted on cultured neural cells had supported that CNR1/CBR (cannabinoid receptor 1), the main molecular target of cannabis, affects macroautophagy/autophagy.

Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination.

The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo.

Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.

Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB receptors, degrade endocannabinoids, and modulate endocannabinergic transmission.

Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

Background: The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

Methods: We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.

Pathway-Specific Control of Striatal Neuron Vulnerability by Corticostriatal Cannabinoid CB1 Receptors.

The vast majority of neurons within the striatum are GABAergic medium spiny neurons (MSNs), which receive glutamatergic input from the cortex and thalamus, and form two major efferent pathways: the direct pathway, expressing dopamine D1 receptor (D1R-MSNs), and the indirect pathway, expressing dopamine D2 receptor (D2R-MSNs). While molecular mechanisms of MSN degeneration have been identified in animal models of striatal damage, the molecular factors that dictate a selective vulnerability of D1R-MSNs or D2R-MSNs remain unknown. Here, we combined genetic, chemogenetic, and pharmacological strategies with behavioral and neurochemical analyses, and show that the pool of cannabinoid CB1 receptor (CB1R) located on corticostriatal terminals efficiently safeguards D1R-MSNs, but not D2R-MSNs, from different insults.

Sustained Gq-Protein Signaling Disrupts Striatal Circuits via JNK.

Unlabelled: The dorsal striatum is a major input structure of the basal ganglia and plays a key role in the control of vital processes such as motor behavior, cognition, and motivation. The functionality of striatal neurons is tightly controlled by various metabotropic receptors. Whereas the G/G-protein-dependent tuning of striatal neurons is fairly well known, the precise impact and underlying mechanism of G-protein-dependent signals remain poorly understood.

Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disease characterized by a progressive decline in motor abilities, as well as in cognitive and social behaviors. Most of these behavioral deficits are recapitulated in the R6/1 transgenic mouse, which can therefore be used as an experimental model to identify the neurobiological substrates of HD pathology and to design novel therapeutic approaches. The endocannabinoid system (ECS) is a relevant candidate to participate in the etiopathology of HD as it is a key modulator of brain function, especially in areas primarily affected by HD dysfunction such as the striatum.