scholarly journals Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

2020 ◽  
Vol 21 (3) ◽  
pp. 908 ◽  
Author(s):  
Silvia Pelucchi ◽  
Ramona Stringhi ◽  
Elena Marcello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Actin Cytoskeleton ◽  
Dendritic Spine ◽  
Neurodegenerative Disorder ◽  
Synaptic Strength ◽  
Synaptic Activity ◽  
Therapeutic Interventions ◽  
Actin Dynamics ◽  
Synaptic Failure

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD.

scholarly journals Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Qingwei Huo ◽  
Sumaiya Tabassum ◽  
Jinxiang Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Morphology ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

scholarly journals In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 54-68 ◽  
Author(s):  
Kanzal Iman ◽  
Muhammad Usman Mirza ◽  
Nauman Mazhar ◽  
Michiel Vanmeert ◽  
Imran Irshad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
Neurodegenerative Disorder ◽  
In Silico Analysis ◽  
Acetylcholinesterase Inhibitors ◽  
Binding Energies ◽  
Therapeutic Interventions ◽  
Ache Inhibitors

Objective and Background: Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site as an allosteric regulator of AChE. Characterized by the formation of β-amyloid plaques, Alzheimer's disease (AD) is currently one of the leading causes of death across the world. Progression in this neurodegenerative disorder causes deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function. The multifactorial AD pathology calls for Multitarget-directed ligands (MTDLs) to follow up on various components of the disease. Considering this approach, other related AD targets were also selected. Structure-based virtual screening was relied upon for the identification of lead compounds with anti-AD effect. Method: Several chemoinformatics approaches were used in this study, reporting four multi-target inhibitors: MCULE-7149246649-0-1, MCULE-6730554226-0-4, MCULE-1176268617-0-6 and MCULE-8592892575-0-1 with high binding energies that indicate better AChE inhibitory activity. Additional in-silico analysis hypothesized the abundant presence of aromatic interactions to be pivotal for interaction of selected compounds to the acetyl-cholinesterase. Additionally, we presented an alternative approach to determine protein-ligand stability by calculating the Gibbs-free energy change over time. Furthermore, this allows to rank potential hits for further in-vitro testing. Results and Conclusion: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

Strategies Targeting Soluble β-Amyloid Oligomers and their Application to Early Diagnosis of Alzheimer’s Disease

2020 ◽  
Vol 16 (12) ◽  
pp. 1132-1142 ◽  
Author(s):  
Fantian Zeng ◽  
Yuyan Li ◽  
Yungen Xu ◽  
Jian Yang ◽  
Zhengshi Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Therapeutic Interventions ◽  
Detection Methods ◽  
Fluorescence Probes ◽  
Amyloid Oligomers ◽  
Β Amyloid

Background: Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, and it is still incurable. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. Mounting evidence indicates that the neurotoxic effects might be attributed to Soluble β-Amyloid Oligomers (SAβO). The SAβO are believed to be neurotoxic peptides more predominant than Aβ plaques in the early stage, and their key role in AD is self-evident. Unfortunately, identification of SAβO proves to be difficult due to their heterogeneous and transient nature. In spite of many obstacles, multiple techniques have recently been developed to target SAβO effectively. This review focuses on the recent progress in the approaches towards SAβO detection in order to shed some light on the future development of SAβO assays. Methods : Literatures were obtained from the following libraries: Web of Science, PubMed, EPO, SIPO, USPTO. Articles were critically reviewed based on their titles, abstracts, and contents. Results: A total of 85 papers are referenced in the review. Results are divided into three categories based on the types of detection methods: small molecule fluorescence probes, oligomer-specific antibodies and electrochemical biosensors. Finally, the improvements and challenges of these approaches applied in the early diagnosis of AD were discussed. Conclusion: This review article covers three kinds of strategies that could be translated into clinic practice and lead to earlier diagnosis and therapeutic interventions of AD.

scholarly journals Synaptic activity prompts γ-secretase–mediated cleavage of EphA4 and dendritic spine formation

2009 ◽  
Vol 185 (3) ◽  
pp. 551-564 ◽  
Author(s):  
Eiji Inoue ◽  
Maki Deguchi-Tawarada ◽  
Aki Togawa ◽  
Chiyuki Matsui ◽  
Kohei Arita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Intracellular Signaling ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Synaptic Activity ◽  
Progressive Decline ◽  
Spine Formation ◽  
Receptor Family

Alzheimer's disease is an age-dependent neurodegenerative disorder that is characterized by a progressive decline in cognitive function. γ-secretase dysfunction is evident in many cases of early onset familial Alzheimer's disease. However, the mechanism by which γ-secretase dysfunction results in memory loss and neurodegeneration is not fully understood. Here, we demonstrate that γ-secretase is localized at synapses and regulates spine formation. We identify EphA4, one of the Ephrin receptor family members, as a substrate of γ-secretase, and find that EphA4 processing is enhanced by synaptic activity. Moreover, overexpression of EphA4 intracellular domain increases the number of dendritic spines by activating the Rac signaling pathway. These findings reveal a function for EphA4-mediated intracellular signaling in the morphogenesis of dendritic spines and suggest that the processing of EphA4 by γ-secretase affects the pathogenesis of Alzheimer's disease.

scholarly journals Sirtuins as Potential Therapeutic Targets for Mitigating Neuroinflammation Associated With Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Kurukulasooriya Kavindya Madushani Fernando ◽  
Yasanandana Supunsiri Wijayasinghe
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Neurodegenerative Disorder ◽  
Therapeutic Interventions ◽  
Cellular Processes ◽  
Dependent Protein ◽  
The Central Nervous System ◽  
Β Amyloid ◽  
With Memory

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which is associated with memory deficit and global cognitive decline. Age is the greatest risk factor for AD and, in recent years, it is becoming increasingly appreciated that aging-related neuroinflammation plays a key role in the pathogenesis of AD. The presence of β-amyloid plaques and neurofibrillary tangles are the primary pathological hallmarks of AD; defects which can then activate a cascade of molecular inflammatory pathways in glial cells. Microglia, the resident macrophages in the central nervous system (CNS), are the major triggers of inflammation; a response which is typically intended to prevent further damage to the CNS. However, persistent microglial activation (i.e., neuroinflammation) is toxic to both neurons and glia, which then leads to neurodegeneration. Growing evidence supports a central role for sirtuins in the regulation of neuroinflammation. Sirtuins are NAD+-dependent protein deacetylases that modulate a number of cellular processes associated with inflammation. This review examines the latest findings regarding AD-associated neuroinflammation, mainly focusing on the connections among the microglial molecular pathways of inflammation. Furthermore, we highlight the biology of sirtuins, and their role in neuroinflammation. Suppression of microglial activity through modulation of the sirtuin activity has now become a key area of research, where progress in therapeutic interventions may slow the progression of Alzheimer’s disease.

scholarly journals Current Perspectives regarding Stem Cell-Based Therapy for Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Kyeong-Ah Kwak ◽  
Seung-Pyo Lee ◽  
Jin-Young Yang ◽  
Young-Seok Park
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Stem Cell ◽  
Small Molecules ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Cell Based Therapy ◽  
Synaptic Failure ◽  
Excessive Accumulation

Alzheimer’s disease (AD), a progressive neurodegenerative disorder featuring memory loss and cognitive impairment, is caused by synaptic failure and the excessive accumulation of misfolded proteins. Many unsuccessful attempts have been made to develop new small molecules or antibodies to intervene in the disease’s pathogenesis. Stem cell-based therapies cast a new hope for AD treatment as a replacement or regeneration strategy. The results from recent preclinical studies regarding stem cell-based therapies are promising. Human clinical trials are now underway. However, a number of questions remain to be answered prior to safe and effective clinical translation. This review explores the pathophysiology of AD and summarizes the relevant stem cell research according to cell type. We also briefly summarize related clinical trials. Finally, future perspectives are discussed with regard to their clinical applications.

scholarly journals Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Andrea Stojakovic ◽  
Sergey Trushin ◽  
Anthony Sheu ◽  
Layla Khalili ◽  
Su-Youne Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Efficacy ◽  
Complex I ◽  
Neurodegenerative Disorder ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
System Response ◽  
Female Mice ◽  
Partial Inhibition

AbstractAlzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

scholarly journals Connectomic Analysis of Alzheimer’s Disease using Percolation Theory

2021 ◽  
pp. 1-48
Author(s):  
Parker Kotlarz ◽  
Juan C. Nino ◽  
Marcelo Febo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Percolation Theory ◽  
Neurodegenerative Disorder ◽  
Brain Network ◽  
Therapeutic Interventions ◽  
Core Network ◽  
Compensatory Response ◽  
Attack Model ◽  
And Control

Abstract Alzheimer’s disease (AD) is a severe neurodegenerative disorder that affects a growing worldwide elderly population. Identification of brain functional biomarkers is expected to help determine preclinical stages for targeted mechanistic studies and development of therapeutic interventions to deter disease progression. Connectomic analysis, a graph theory-based methodology used in the analysis of brain-derived connectivity matrices was used in conjunction with percolation theory targeted attack model to investigate the network effects of AD-related amyloid deposition. We used matrices derived from resting state functional magnetic resonance imaging collected on mice with extracellular amyloidosis (TgCRND8 mice, n = 17) and control littermates (n = 17). Global, nodal, spatial, and percolation-based analysis was performed comparing AD and control mice. These data indicate a short-term compensatory response to neurodegeneration in the AD brain via a strongly connected core network with highly vulnerable or disconnected hubs. Targeted attacks demonstrated a greater vulnerability of AD brains to all types of attacks and identified progression models to mimic AD brain functional connectivity through betweenness centrality and collective influence metrics. Furthermore, both spatial analysis and percolation theory identified a key disconnect between the anterior brain of the AD mice to the rest of the brain network.

Auditory Dysfunction in Alzheimer's Disease

2010 ◽  
Vol 15 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Sridhar Krishnamurti
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Health Care ◽  
Care Setting ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Clinical Protocols ◽  
Speech Language Pathologist ◽  
Auditory Dysfunction

Alzheimer's disease is neurodegenerative disorder which affects a growing number of older adults every year. With an understanding of auditory dysfunction in Alzheimer's disease, the speech-language pathologist working in the health care setting can provide better service to these individuals. The pathophysiology of the disease process in Alzheimer's disease increases the likelihood of specific types of auditory deficits as opposed to others. This article will discuss the auditory deficits in Alzheimer's disease, their implications, and the value of clinical protocols for individuals with this disease.

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