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GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, brain atrophy due to neuronal and synapse loss, and formation of two pathological lesions: extracellular amyloid plaques, composed largely of amyloid-beta peptide (A?), and neurofibrillary tangles formed by intracellular aggregates of hyperphosphorylated tau protein. Lesions mainly accumulate in brain regions that modulate cognitive functions such as the hippocampus, septum or amygdala. These brain structures have dense reciprocal glutamatergic, cholinergic, and GABAergic connections and their relationships directly affect learning and memory processes, so they have been proposed as highly susceptible regions to suffer damage by A? during AD course. Last findings support the emerging concept that soluble A? peptides, inducing an initial stage of synaptic dysfunction which probably starts 20-30 years before the clinical onset of AD, can perturb the excitatory-inhibitory balance of neural circuitries. In turn, neurotransmission imbalance will result in altered network activity that might be responsible of cognitive deficits in AD. Therefore, A? interactions on neurotransmission systems in memory-related brain regions such as amygdaloid complex, medial septum or hippocampus are critical in cognitive functions and appear as a pivotal target for drug design to improve learning and dysfunctions that manifest with age. Since treatments based on glutamatergic and cholinergic pharmacology in AD have shown limited success, therapies combining modulators of different neurotransmission systems including recent findings regarding the GABAergic system, emerge as a more useful tool for the treatment, and overall prevention, of this dementia. In this review, focused on inhibitory systems, we will analyze pharmacological strategies to compensate neurotransmission imbalance that might be considered as potential therapeutic interventions in AD.

SUBMITTER: Nava-Mesa MO

PROVIDER: S-EPMC4070063 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer's disease.

Nava-Mesa Mauricio O MO Jiménez-Díaz Lydia L Yajeya Javier J Navarro-Lopez Juan D JD

Frontiers in cellular neuroscience 20140625

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, brain atrophy due to neuronal and synapse loss, and formation of two pathological lesions: extracellular amyloid plaques, composed largely of amyloid-beta peptide (Aβ), and neurofibrillary tangles formed by intracellular aggregates of hyperphosphorylated tau protein. Lesions mainly accumulate in brain regions that modulate cognitive functions such as the hippocampus, septum or amygdala. These ...[more]

PMID: 24987334

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Project description:BackgroundPerivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown.ObjectiveWe aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors.MethodsThe study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071).ResultsThe degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants.ConclusionsOur results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.

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GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer's disease.

Publications

GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer's disease.

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