Electrical stimulation of the medial forebrain bundle as a potential therapy for alzheimer's disease: effects on molecular markers in rodent model

• Autores: Irene Puig Parnau
• Directores de la Tesis: Gemma Huguet (dir. tes.), Pilar Segura (codir. tes.), Elisabeth Kádár García (codir. tes.)
• Lectura: En la Universitat de Girona ( España ) en 2021
• Idioma: español
• Tribunal Calificador de la Tesis: José Rodríguez Alvarez (presid.), Pere Boadas Vaello (secret.), Antoni Turon Estrada (voc.)
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• Resumen

  • Alzheimer’s disease (AD) is the most common cause of dementia, mainly characterized by episodic memory disturbances among other disabling symptoms. Despite great efforts put in AD research, at present there is no treatment able to cure or stop the progression of the disease. In this situation, electrical stimulation of deep brain areas (deep brain stimulation, DBS) has been suggested as a novel neuromodulatory approach to restore memory circuits in AD. Although the biological mechanisms underlying this treatment are not completely understood, DBS aimed at different brain targets has shown promising results of cognitive efficacy in AD context, both in studies using experimental animals as well as in initial clinical trials. However, the election of the target region remains a critical controversial issue.

    Previous studies from our group have demonstrated that stimulation of the medial forebrain bundle, an area part of the neural substrate of reward, facilitates learning and memory in healthy adult rats, as well as in rats with age- or lesion-related memory impairment. Hypothesizing that stimulation to this area (designated as MFB-ICSS) could be also effective in AD condition, this thesis assesses the effect of MFB-ICSS on AD-related molecules, as well as its relation with cognitive outcome, in a rat model.

    Obtained results have confirmed that MFB-ICSS modulates AD-related molecules and facilitates memory in this condition. In this regard, levels of central molecules in AD etiopathology, like amyloid precursor protein (APP) or phosphorylated tau, have been found decreased in the hippocampus of treated rats. Additionally, an increase in neuronal density has been also reported. Furthermore, MFB-ICSS effect on key gene expression regulators like SIRT1 protein and particular microRNAs, all of them associated with learning and memory and altered in AD, has been described for the first time. Particularly, effects on miR-132 and SIRT1 have been observed not only in the hippocampus, but also in blood serum. This data is especially interesting regarding the potential use of these molecules as non-invasive treatment biomarkers. Finally, this thesis also provides an evaluation of sporadic AD models used in the constituting studies, including amyloid-β- and streptozotocin-injected models.

    Altogether, this work evidences that MFB-ICSS mechanisms intercede with molecular markers of AD. Even though there is a long way to go, these results sustain the promising potential of rewarding stimulation of the medial forebrain bundle as a treatment for Alzheimer’s disease.