Current and emerging avenues for Alzheimer's disease drug targets

Abstract

Loera-Valencia R, Cedazo-Minguez A, ). Current and emerging avenues for Alzheimer's disease drug targets (Review). J Intern Med 2019; 286: 398-437.Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Ab) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Ab and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy. ReviewInsoluble Ab fibrils are taken into consideration as the main responsible for spine pathology. On the other hand, in both transgenic mouse models of AD and human AD brain, synapse defects and memory loss correlate weakly with the presence of Ab Current and novel Alzheimer´s disease therapy targets / R. Loera-Valencia et al.

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…Pathological Aβ accumulation in the kidneys (Gronewold et al, 2017) may result in filtration disorder. Although various signaling molecules have been identified as possible targets in the treatment of this neurodegeneration process (Loera-Valencia et al, 2019;Patel et al, 2019), the complexity of AD makes drug development difficult. Limited data show the importance of physical activity in postponing the manifestation of characteristic AD (Radak et al, 2010;Abraham et al, 2019).…”

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

“…Among these pathological processes, Aβ remains the most prominent target in clinical trials of disease-modifying drug candidates against AD [8], both at the symptomatic and the preclinical stage. Exactly what starts the process of concentration-dependent initiation of prion-like Aβ misfolding due to increased production and/or defective Aβ clearance, is presently unclear, but a wealth of experimental and observational data suggest that Aβ accumulation is not an innocent by-stander but toxic to synapses and neurons [9].…”

A Randomized, Double Blind, Vehicle Controlled, Parallel, Phase Ii Study to Evaluate Efficacy and Safety of Bac in Patients With Alzheimer’s Disease or Vascular Dementia

“…Secondary endpoints included changes in ADAS-cog score at other visits; CIBIC-plus score at all visits, which is the Clinician's Interview-Based Impression of Severity/Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIS/CIBIC-Plus), a widely used in anti-dementia drug trials for global assessment in the outcome measurement [17]; change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Inventory compared to baseline, which measures the competence of patients with AD in their basic and instrumental activities of daily living [20]; change in Mini-Mental State Examination (MMSE) at all visits compared to baseline, which evaluates cognitive functions among elderly on orientation, attention, memory, language, and visual-spatial skills [21]; and change in Neuropsychiatric Instrument (NPI) score compared to baseline, which assesses neuropsychiatric symptoms and psychopathology of patients with AD and other neurodegenerative disorders.…”