Una revisión de los avances en la terapéutica de la enfermedad de Alzheimer: estrategia frente a la proteína Beta-amiloide / Review of the advances in treatment for Alzheimer disease: Strategies for combating Beta-amyloid protein

Introducción: La enfermedad de Alzheimer (EA) es el principal trastorno neurodegenerativo que provoca una discapacidad intelectual total en los pacientes que la presentan. La elevada prevalencia a nivel mundial, así como la elevada carga socioeconómica que conlleva la EA para la sociedad en general, hace que sea considerada un importante problema de salud pública en este siglo xxi. En este trabajo se revisan los tratamientos actuales y en fase de desarrollo que actúan principalmente sobre la proteína Beta-amiloide. Discusión: La hipótesis amiloidogénica propone que el péptido β-amiloide tiene un papel clave en esta enfermedad. Se han desarrollado varias estrategias farmacológicas diferentes con el objetivo de inhibir la formación de los péptidos β-amiloides, como son los inhibidores de Beta-secretasa y γ-secretasa. Además, se han desarrollado los tratamientos antiamiloide, que incluyen inmunoterapias pasivas y activas enfocadas a inhibir la agregación del péptido Beta-amiloide. Conclusiones: Los avances en la identificación de las bases moleculares de la EA pueden servir como modelo para comprender las causas de esta enfermedad neurodegenerativa. Sin embargo, los ensayos clínicos más recientes en 2 ensayos de fase iii con solanezumab, un anticuerpo monoclonal humanizado que promueve el aclaramiento del Beta-amiloide en el cerebro, indican que este anticuerpo no muestra eficacia en pacientes con EA leve, sugiriendo que hay que replantearse esta hipótesis amiloidogénica de la EA (AU)

Introduction: Alzheimer disease (AD) is a major neurodegenerative disorder which eventually results in total intellectual disability. The high global prevalence and the socioeconomic burden associated with the disease pose major challenges for public health in the 21st century. In this review we focus on both existing treatments and the therapies being developed, which principally target the Beta-amyloid protein. Discussion: The amyloidogenic hypothesis proposes that Beta-amyloid plays a key role in AD. Several pharmacological approaches aim to reduce the formation of Beta-amyloid peptides by inhibiting the Beta-secretase and γ-secretase enzymes. In addition, both passive and active immunotherapies have been developed for the purpose of inhibiting β-amyloid peptide aggregation. Conclusions: Progress in identifying the molecular basis of AD may provide better models for understanding the causes of this neurodegenerative disease. The lack of efficacy of solanezumab (a humanised monoclonal antibody that promotes Beta-amyloid clearance in the brain), demonstrated by 2 recent Phase III clinical trials in patients with mild AD, suggests that the amyloidogenic hypothesis needs to be revised (AU)

Review of the advances in treatment for Alzheimer disease: Strategies for combating ß-amyloid protein. / Una revisión de los avances en la terapéutica de la enfermedad de Alzheimer: estrategia frente a la proteína ß-amiloide.

INTRODUCTION: Alzheimer disease (AD) is a major neurodegenerative disorder which eventually results in total intellectual disability. The high global prevalence and the socioeconomic burden associated with the disease pose major challenges for public health in the 21st century. In this review we focus on both existing treatments and the therapies being developed, which principally target the ß-amyloid protein. DISCUSSION: The amyloidogenic hypothesis proposes that ß-amyloid plays a key role in AD. Several pharmacological approaches aim to reduce the formation of ß-amyloid peptides by inhibiting the ß-secretase and γ-secretase enzymes. In addition, both passive and active immunotherapies have been developed for the purpose of inhibiting ß-amyloid peptide aggregation. CONCLUSIONS: Progress in identifying the molecular basis of AD may provide better models for understanding the causes of this neurodegenerative disease. The lack of efficacy of solanezumab (a humanised monoclonal antibody that promotes ß-amyloid clearance in the brain), demonstrated by 2 recent Phase III clinical trials in patients with mild AD, suggests that the amyloidogenic hypothesis needs to be revised.

Adipokine pathways are altered in hippocampus of an experimental mouse model of Alzheimer's disease.

A growing body of evidence suggests that ß-amyloid peptides (Aß) are unlikely to be the only factor involved in Alzheimer's disease (AD) aetiology. In fact, a strong correlation has been established between AD patients and patients with type 2 diabetes and/or cholesterol metabolism alterations. In addition, a link between adipose tissue metabolism, leptin signalling in particular, and AD has also been demonstrated. In the present study we analyzed the expression of molecules related to metabolism, with the main focus on leptin and prolactin signalling pathways in an APPswe/PS1dE9 (APP/PS1) transgenic mice model, at 3 and 6 months of age, compared to wild-type controls. We have chosen to study 3 months-old APP/PS1 animals at an age when neither the cognitive deficits nor significant Aß plaques in the brain are present, and to compare them to the 6 months-old mice, which exhibit elevated levels of Aß in the hippocampus and memory loss. A significant reduction in both mRNA and protein levels of the prolactin receptor (PRL-R) was detected in the hippocampi of 3 months old APP/PS1 mice, with a decrease in the levels of the leptin receptor (OB-R) first becoming evident at 6 months of age. We proceeded to study the expression of the intracellular signalling molecules downstream of these receptors, including stat (1-5), sos1, kras and socs (1-3). Our data suggest a downregulation in some of these molecules such as stat-5b and socs (1-3), in 3 months-old APP/PS1 brains. Likewise, at the same age, we detected a significant reduction in mRNA levels of lrp1 and cyp46a1, both of which are involved in cholesterol homeostasis. Taken together, these results demonstrate a significative impairment in adipokine receptors signalling and cholesterol regulation pathways in the hippocampus of APP/PS1 mice at an early age, prior to the Aß plaque formation.