Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015 ◽  
Vol 51 (70) ◽  
pp. 13434-13450 ◽  
Author(s):  
K. Rajasekhar ◽  
Malabika Chakrabarti ◽  
T. Govindaraju
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Physiological Role ◽  
Therapeutic Interventions ◽  
Toxic Effects ◽  
Feature Article ◽  
Therapeutic Molecules

Our Feature Article details the physiological role of amyloid beta (Aβ), elaborates its toxic effects and outlines therapeutic molecules designed in the last two years targeting different aspects of Aβ for preventing AD.

scholarly journals Computational Modeling of Catecholamines Dysfunction in Alzheimer’s Disease at Pre-Plaque Stage

2020 ◽  
Vol 77 (1) ◽  
pp. 275-290
Author(s):  
Daniele Caligiore ◽  
Massimo Silvetti ◽  
Marcello D’Amelio ◽  
Stefano Puglisi-Allegra ◽  
Gianluca Baldassarre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Catecholamine Release ◽  
Therapeutic Interventions ◽  
System Level ◽  
Amyloid Cascade Hypothesis ◽  
Neural Data ◽  
Sequence Of Events ◽  
Amyloid Cascade

Background: Alzheimer’s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

scholarly journals Zinc-mediated Neurotransmission in Alzheimer's Disease: A Potential Role of the GPR39 in Dementia

2019 ◽  
Vol 18 (1) ◽  
pp. 2-13
Author(s):  
Michal Rychlik ◽  
Katarzyna Mlyniec
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Neural Plasticity ◽  
Modern Society ◽  
Neuroprotective Drugs ◽  
Age Related ◽  
Candidate Drug ◽  
G Protein Coupled

: With more people reaching an advanced age in modern society, there is a growing need for strategies to slow down age-related neuropathology and loss of cognitive functions, which are a hallmark of Alzheimer's disease. Neuroprotective drugs and candidate drug compounds target one or more processes involved in the neurodegenerative cascade, such as excitotoxicity, oxidative stress, misfolded protein aggregation and/or ion dyshomeostasis. A growing body of research shows that a G-protein coupled zinc (Zn2+) receptor (GPR39) can modulate the abovementioned processes. : Zn2+itself has a diverse activity profile at the synapse, and by binding to numerous receptors, it plays an important role in neurotransmission. However, Zn2+ is also necessary for the formation of toxic oligomeric forms of amyloid beta, which underlie the pathology of Alzheimer’s disease. Furthermore, the binding of Zn2+ by amyloid beta causes a disruption of zincergic signaling, and recent studies point to GPR39 and its intracellular targets being affected by amyloid pathology. : In this review, we present neurobiological findings related to Zn2+ and GPR39, focusing on its signaling pathways, neural plasticity, interactions with other neurotransmission systems, as well as on the effects of pathophysiological changes observed in Alzheimer's disease on GPR39 function. : Direct targeting of the GPR39 might be a promising strategy for the pharmacotherapy of zincergic dyshomeostasis observed in Alzheimer’s disease. The information presented in this article will hopefully fuel further research into the role of GPR39 in neurodegeneration and help in identifying novel therapeutic targets for dementia.

P4-036: Role of nitric oxide and arachidonic acid release and metabolism in Alzheimer's disease amyloid beta toxicity

2006 ◽  
Vol 2 ◽  
pp. S524-S524
Author(s):  
Joanna B. Strosznajder ◽  
Joanna Glowacka ◽  
Alicja Zabielna ◽  
Malgorzata Chalimoniuk
Keyword(s):  
Nitric Oxide ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Arachidonic Acid ◽  
Amyloid Beta ◽  
Arachidonic Acid Release ◽  
Acid Release

scholarly journals Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

2021 ◽  
Vol 15 ◽  
Author(s):  
Guimei Zhang ◽  
Zicheng Wang ◽  
Huiling Hu ◽  
Meng Zhao ◽  
Li Sun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Age Related ◽  
Amyloid Accumulation ◽  
Pathophysiological Role ◽  
Inflammatory Drugs ◽  
Β Amyloid

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

scholarly journals The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

2019 ◽  
Vol 3 (2) ◽  
Author(s):  
Holly C. Hunsberger ◽  
Priyanka D. Pinky ◽  
Warren Smith ◽  
Vishnu Suppiramaniam ◽  
Miranda N. Reed
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synapse Formation ◽  
Late Onset ◽  
Therapeutic Interventions ◽  
Memory Decline ◽  
Current Therapies ◽  
Ε4 Allele ◽  
The Impact

Abstract Alzheimer’s disease (AD) is the leading cause of dementia affecting almost 50 million people worldwide. The ε4 allele of Apolipoprotein E (APOE) is the strongest known genetic risk factor for late-onset AD cases, with homozygous APOE4 carriers being approximately 15-times more likely to develop the disease. With 25% of the population being APOE4 carriers, understanding the role of this allele in AD pathogenesis and pathophysiology is crucial. Though the exact mechanism by which ε4 allele increases the risk for AD is unknown, the processes mediated by APOE, including cholesterol transport, synapse formation, modulation of neurite outgrowth, synaptic plasticity, destabilization of microtubules, and β-amyloid clearance, suggest potential therapeutic targets. This review will summarize the impact of APOE on neurons and neuronal signaling, the interactions between APOE and AD pathology, and the association with memory decline. We will then describe current treatments targeting APOE4, complications associated with the current therapies, and suggestions for future areas of research and treatment.

Navigating Alzheimer’s Disease via Chronic Stress: The Role of Glucocorticoids

2020 ◽  
Vol 21 (5) ◽  
pp. 433-444 ◽  
Author(s):  
Vivek Kumar Sharma ◽  
Thakur Gurjeet Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Stress ◽  
Glucocorticoid Receptors ◽  
Molecular Mechanisms ◽  
Senile Plaques ◽  
Symptomatic Relief ◽  
Therapeutic Interventions ◽  
Physiological Status

Alzheimer’s disease (AD) is a chronic intensifying incurable progressive disease leading to neurological deterioration manifested as impairment of memory and executive brain functioning affecting the physical ability like intellectual brilliance, common sense in patients. The recent therapeutic approach in Alzheimer's disease is only the symptomatic relief further emerging the need for therapeutic strategies to be targeted in managing the underlying silent killing progression of dreaded pathology. Therefore, the current research direction is focused on identifying the molecular mechanisms leading to the evolution of the understanding of the neuropathology of Alzheimer's disease. The resultant saturation in the area of current targets (amyloid β, τ Protein, oxidative stress etc.) has led the scientific community to rethink of the mechanistic neurodegenerative pathways and reprogram the current research directions. Although, the role of stress has been recognized for many years and contributing to the development of cognitive impairment, the area of stress has got the much-needed impetus recently and is being recognized as a modifiable menace for AD. Stress is an unavoidable human experience that can be resolved and normalized but chronic activation of stress pathways unsettle the physiological status. Chronic stress mediated activation of neuroendocrine stimulation is generally linked to a high risk of developing AD. Chronic stress-driven physiological dysregulation and hypercortisolemia intermingle at the neuronal level and leads to functional (hypometabolism, excitotoxicity, inflammation) and anatomical remodeling of the brain architecture (senile plaques, τ tangles, hippocampal atrophy, retraction of spines) ending with severe cognitive deterioration. The present review is an effort to collect the most pertinent evidence that support chronic stress as a realistic and modifiable therapeutic earmark for AD and to advocate glucocorticoid receptors as therapeutic interventions.

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