scholarly journals Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Simona Magi ◽  
Pasqualina Castaldo ◽  
Maria Loredana Macrì ◽  
Marta Maiolino ◽  
Alessandra Matteucci ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Intracellular Calcium ◽  
Calcium Homeostasis ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Calcium Stores ◽  
Cellular Mechanisms ◽  
Calcium Dysregulation ◽  
Review Reports

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-βplaques within the brain. Together with plaques deposition, the hyperphosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level.

scholarly journals Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

2021 ◽  
Vol 10 (8) ◽  
pp. 1555
Author(s):  
Ágoston Patthy ◽  
János Murai ◽  
János Hanics ◽  
Anna Pintér ◽  
Péter Zahola ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Brain Structures ◽  
Specific Information ◽  
Cellular Mechanisms ◽  
Monoaminergic System ◽  
Monoaminergic Neurons

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

scholarly journals Increased expression of heme-binding protein 1 early in Alzheimer's disease is linked to neurotoxicity

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Oleksandr Yagensky ◽  
Mahdokht Kohansal-Nodehi ◽  
Saravanan Gunaseelan ◽  
Tamara Rabe ◽  
Saima Zafar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Binding Protein ◽  
Neuronal Loss ◽  
Heme Binding ◽  
Brain Proteome ◽  
Induced Apoptosis ◽  
Proteome Changes ◽  
Heme Binding Protein

Alzheimer’s disease is the most prevalent neurodegenerative disorder leading to progressive cognitive decline. Despite decades of research, understanding AD progression at the molecular level, especially at its early stages, remains elusive. Here, we identified several presymptomatic AD markers by investigating brain proteome changes over the course of neurodegeneration in a transgenic mouse model of AD (3×Tg-AD). We show that one of these markers, heme-binding protein 1 (Hebp1), is elevated in the brains of both 3×Tg-AD mice and patients affected by rapidly-progressing forms of AD. Hebp1, predominantly expressed in neurons, interacts with the mitochondrial contact site complex (MICOS) and exhibits a perimitochondrial localization. Strikingly, wildtype, but not Hebp1-deficient, neurons showed elevated cytotoxicity in response to heme-induced apoptosis. Increased survivability in Hebp1-deficient neurons is conferred by blocking the activation of the mitochondrial-associated caspase signaling pathway. Taken together, our data highlight a role of Hebp1 in progressive neuronal loss during AD progression.

scholarly journals YKL-40 as a Potential Biomarker for the Differential Diagnosis of Alzheimer’s Disease

Medicina ◽  
2021 ◽  
Vol 58 (1) ◽  
pp. 60
Author(s):  
Ioannis Mavroudis ◽  
Rumana Chowdhury ◽  
Foivos Petridis ◽  
Eleni Karantali ◽  
Symela Chatzikonstantinou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Diagnosis ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Cochrane Library ◽  
Potential Biomarker ◽  
The Cochrane Library

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, associated with extensive neuronal loss, dendritic and synaptic changes resulting in significant cognitive impairment. An increased number of studies have given rise to the neuroinflammatory hypothesis in AD. It is widely accepted that AD brains show chronic inflammation, probably triggered by the presence of insoluble amyloid beta deposits and neurofibrillary tangles (NFT) and is also related to the activation of neuronal death cascade. In the present study we aimed to investigate the role of YKL-40 levels in the cerebrospinal fluid (CSF) in the diagnosis of AD, and to discuss whether there are further potential roles of this protein in the management and treatment of AD. We conducted an online search on PubMed, Web of Science, and the Cochrane library databases from 1990 to 2021. The quantitative analysis showed that the levels of YKL-40 were significantly higher in Alzheimer’s disease compared to controls, to mild cognitive impairment (MCI) AD (MCI-AD) and to stable MCI. They were also increased in MCI-AD compared to stable MCI. The present study shows that the CSF levels of YKL-40 could be potentially used as a biomarker for the prognosis of mild cognitive impairment and the likelihood of progression to AD, as well as for the differential diagnosis between AD and MCI.

Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer’s disease

2019 ◽  
Vol 32 (2) ◽  
pp. 65-71 ◽  
Author(s):  
Anila Venugopal ◽  
Mahalaxmi Iyer ◽  
Venkatesh Balasubramanian ◽  
Balachandar Vellingiri
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Calcium Homeostasis ◽  
Therapeutic Strategy ◽  
Neurodegenerative Disorder ◽  
Amyloid Plaque ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter

AbstractAlzheimer’s disease (AD), a neurodegenerative disorder, is the leading cause of dementia in the world whose aetiology is still unclear. AD was always related to ageing though there have been instances where people at an early age also succumb to this disease. With medical advancements, the mortality rate has significantly reduced which also makes people more prone to AD. AD is rare, yet the prominent disease has been widely studied with several hypotheses trying to understand the workings of its onset. The most recent and popular hypothesis in AD is the involvement of mitochondrial dysfunction and calcium homeostasis in the development of the disease though their exact roles are not known. With the sudden advent of the mitochondrial calcium uniporter (MCU), many previously known pathological hallmarks of AD may be better understood. Several studies have shown the effect of excess calcium in mitochondria and the influence of MCU complex in mitochondrial function. In this article, we discuss the possible involvement of MCU in AD by linking the uniporter to mitochondrial dysfunction, calcium homeostasis, reactive oxygen species, neurotransmitters and the hallmarks of AD – amyloid plaque formation and tau tangle formation.

scholarly journals Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice

2000 ◽  
Vol 149 (4) ◽  
pp. 793-798 ◽  
Author(s):  
Malcolm A. Leissring ◽  
Yama Akbari ◽  
Christopher M. Fanger ◽  
Michael D. Cahalan ◽  
Mark P. Mattson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Brain Aging ◽  
Calcium Entry ◽  
Calcium Stores ◽  
Capacitative Calcium Entry ◽  
Intracellular Calcium Stores ◽  
Agonist Stimulation

Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations.

scholarly journals Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

2019 ◽  
Author(s):  
Viviana Soto-Mercado ◽  
Miguel Mendivil-Perez ◽  
Carlos Velez-Pardo ◽  
Francisco Lopera ◽  
Marlene Jimenez-Del-Rio
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Cholinergic Neurons ◽  
Tau Phosphorylation ◽  
Cellular Mechanisms ◽  
Limited Effectiveness ◽  
Aβ42 Peptide

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra- and extracellular Aβ42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

Retinal Changes in Transgenic Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Li Guo ◽  
Nivedita Ravindran ◽  
Daniel Hill ◽  
M. Francesca Cordeiro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
The Central Nervous System ◽  
New Treatments ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterized by amyloid-ß (Aß) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well-documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations.

scholarly journals An Analysis of the Neurological and Molecular Alterations Underlying the Pathogenesis of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 546
Author(s):  
Chantal Vidal ◽  
Li Zhang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Critical Role ◽  
Neuronal Loss ◽  
Molecular Characteristics ◽  
Barrier Dysfunction ◽  
Molecular Alterations ◽  
Root Cause

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Unfortunately, despite decades of studies being performed on these histological alterations, there is no effective treatment or cure for AD. Identifying the molecular characteristics of the disease is imperative to understanding the pathogenesis of AD. Furthermore, uncovering the key causative alterations of AD can be valuable in developing models for AD treatment. Several alterations have been implicated in driving this disease, including blood–brain barrier dysfunction, hypoxia, mitochondrial dysfunction, oxidative stress, glucose hypometabolism, and altered heme homeostasis. Although these alterations have all been associated with the progression of AD, the root cause of AD has not been identified. Intriguingly, recent studies have pinpointed dysfunctional heme metabolism as a culprit of the development of AD. Heme has been shown to be central in neuronal function, mitochondrial respiration, and oxidative stress. Therefore, dysregulation of heme homeostasis may play a pivotal role in the manifestation of AD and its various alterations. This review will discuss the most common neurological and molecular alterations associated with AD and point out the critical role heme plays in the development of this disease.

scholarly journals Introducing New Neurons in the Alzheimer’s Disease Brain

2021 ◽  
Vol 7 (4) ◽  
pp. 1-6
Author(s):  
CA González ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Elderly Population ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
The Elderly ◽  
Cell Therapies ◽  
The Brain

Alzheimer’s disease is the most prevalent neurodegenerative disorder in the elderly population. The patients suffer cerebral atrophyas a consequence of extensive neuronal loss, especially in areas that play a role in memory and cognition. Cell therapies approaches have emerged as promising treatments to regenerate the brain tissue of the patients

scholarly journals Inhibitory Neural Network’s Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 698
Author(s):  
Hyeon Jeong Seo ◽  
Jung Eun Park ◽  
Seong-Min Choi ◽  
Taekyoung Kim ◽  
Soo Hyun Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Signal Transmission ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.

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