Biology subjects

Gimenez-Llort, L.

Publications and source records attributed to Gimenez-Llort, L..

3 recordsLinked to original sources

bioRxiv2024

Cortical lipids containing choline mediate cannabinoid-induced cognitive improvement

Recent research connecting choline-containing lipids to basal forebrain cholinergic neurons (BFCN) degeneration in neuropathological states highlights a challenge for balancing lipid integrity with optimal acetylcholine (ACh) levels. Warranting an adequate choline source to maintain ACh levels in this pathway is crucial for preserving memory. The endocannabinoid (eCB) system plays a role in modulating learning and memory processes controlled by cholinergic neurotransmission. Consequently, we propose that activation of this system is neuroprotective against cholinergic degeneration. In the present study, we investigated the neuroprotective effect of a subchronic treatment with the CB1 cannabinoid agonist, WIN55,212-2, using both ex vivo and in vivo 192IgG-Saporin models of specific cholinergic damage. Degeneration of baso-cortical cholinergic pathways induced memory deficits and a downregulation of saturated and mono-unsaturated lysophosphatidylcholines (LPC) cortical levels. WIN55,212-2 not only restored memory deficits but also increased cortical ACh levels and modified cortical choline-containing lipids such as sphingomyelins (SM) and LPCs, which are essential for correct memory functioning, in lesioned animals. Given these results, we propose that WIN55,212-2 generates an alternative choline source through the breakdown of SMs, which is enough to increase cortical ACh levels and LPCs. These findings suggest that modification of choline-containing lipids by the activation of CB1 receptors is a promising therapy for dementia associated with cholinergic dysfunction, such as in Alzheimers disease (AD).

neuroscience↗

bioRxiv2024

Nr4a2 blocks oAbeta-mediated synaptic plasticity dysfunction and ameliorates spatial memory deficits in the APPSw,Ind mouse

Alzheimers disease AD is associated with disruptions in neuronal communication, especially in brain regions crucial for learning and memory, such as the hippocampus. The amyloid hypothesis suggests that the accumulation of amyloid-beta oligomers (oA{beta}) contributes to synaptic dysfunction by internalisation of synaptic AMPA receptors. Recently, it has been reported that Nr4a2, a member of the Nr4a family of orphan nuclear receptors, plays a role in hippocampal synaptic plasticity by regulating BDNF and synaptic AMPA receptors. Here, we demonstrate that oA{beta} inhibits activity-dependent Nr4a2 activation in hippocampal neurons, indicating a potential link between oA{beta} and Nr4a2 down-regulation. Furthermore, we have observed a reduction in Nr4a2 protein levels in postmortem hippocampal tissue samples from early AD stages. Pharmacological activation of Nr4a2 proves effective in preventing oA{beta}-mediated synaptic depression in the hippocampus. Notably, Nr4a2 overexpression in the hippocampus of AD mouse models ameliorates spatial learning and memory deficits. In conclusion, the findings suggest that oA{beta} may contribute to early cognitive impairment in AD by blocking Nr4a2 activation, leading to synaptic dysfunction. Thus, our results further support that Nr4a2 activation is a potential therapeutic target to mitigate oA{beta}-induced synaptic and cognitive impairments in the early stages of Alzheimers disease.

neuroscience↗

bioRxiv2023

Modelling human brain-wide pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficits

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinsons, Alzheimers and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model may open new research avenues in brain aging and neurodegeneration.

neuroscience↗