Bridging the Gap between Alzheimer’s Disease and Alzheimer’s-like Diseases in Animals

The average life span steadily grows in humans and in animals kept as pets or left in sanctuaries making the issue of elderly-associated cognitive impairment a hot-spot for scientists. Alzheimer’s disease (AD) is the most prevalent cause of progressive mental deterioration in aging humans, and there is a growing body of evidence that similar disorders (Alzheimer’s-like diseases, ALD) are observed in animals, more than ever found in senescent individuals. This review reveals up to date knowledge in pathogenesis, hallmarks, diagnostic approaches and modalities in AD faced up with ALD related to different animal species. If found at necropsy, there are striking similarities between senile plaques (SP) and neurofibrillary tangles (NFT) in human and animal brains. Also, the set of clinical symptoms in ALD resembles that observed in AD. At molecular and microscopic levels, the human and animal brain histopathology in AD and ALD shows a great resemblance. AD is fatal, and the etiology is still unknown, although the myriad of efforts and techniques were employed in order to decipher the molecular mechanisms of disease onset and its progression. Nowadays, according to an increasing number of cases reported in animals, apparently, biochemistry of AD and ALD has a lot in common. Described observations point to the importance of extensive in vivo models and extensive pre-clinical studies on aging animals as a suitable model for AD disease.

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Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

International Journal of Molecular Sciences ◽

10.3390/ijms222212181 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12181

Author(s):

Guido Santos ◽

Mario Díaz

Keyword(s):

Alzheimer’S Disease ◽

Mathematical Model ◽

Alzheimer's Disease ◽

Human Brain ◽

Lipid Rafts ◽

Brain Cortex ◽

Clinical Symptoms ◽

Senile Plaques ◽

Amyloid Β ◽

Human Brain Cortex

Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.

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PRECISION MEDICINE - THE GOLDEN GATE FOR DETECTION, TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2016.112 ◽

2016 ◽

pp. 1-17

Author(s):

H. Hampel ◽

S.E. O’Bryant ◽

J.I. Castrillo ◽

C. Ritchie ◽

K. Rojkova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Precision Medicine ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

Late Onset ◽

Therapeutic Success ◽

Preclinical Stage ◽

Treatment And Prevention

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

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Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst0390819 ◽

2011 ◽

Vol 39 (3) ◽

pp. 819-822 ◽

Cited By ~ 18

Author(s):

Ana M. Mata ◽

María Berrocal ◽

M. Rosario Sepúlveda

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plasma Membrane ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Senile Plaques ◽

Amyloid Β ◽

Inhibitory Effect ◽

Amyloid Β Peptide ◽

Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

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Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.600084 ◽

2021 ◽

Vol 13 ◽

Author(s):

Audrey Hector ◽

Jonathan Brouillette

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

Epileptiform Activity ◽

Amyloid Β ◽

Gamma Oscillations ◽

Synaptic Activity ◽

Early Stages ◽

The Impact

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

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Supplementation with Curcuma longa Reverses Neurotoxic and Behavioral Damage in Models of Alzheimer’s Disease: A Systematic Review

Current Neuropharmacology ◽

10.2174/0929867325666180117112610 ◽

2019 ◽

Vol 17 (5) ◽

pp. 406-421 ◽

Cited By ~ 7

Author(s):

Ianara Mendonça da Costa ◽

Marco Aurelio de Moura Freire ◽

José Rodolfo Lopes de Paiva Cavalcanti ◽

Dayane Pessoa de Araújo ◽

Bianca Norrara ◽

...

Keyword(s):

Systematic Review ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Curcuma Longa ◽

Senile Plaques ◽

Experimental Models ◽

Cochrane Library

Background: The formation of senile plaques and neurofibrillary tangles of the tau protein are the main pathological mechanism of Alzheimer’s disease (AD). Current therapies for AD offer discrete benefits to the clinical symptoms and do not prevent the continuing degeneration of neuronal cells. Therefore, novel therapeutic strategies have long been investigated, where curcumin (Curcuma longa) has shown some properties that can prevent the deleterious processes involved in neurodegenerative diseases. Objective: The aim of the present work is to review studies that addressed the effects of curcumin in experimental models (in vivo and in vitro) for AD. Method: This study is a systematic review conducted between January and June 2017, in which a consultation of scientific articles from indexed periodicals was carried out in Science Direct, United States National Library of Medicine (PubMed), Cochrane Library and Scielo databases, using the following descriptors: “Curcuma longa”, “Curcumin” and “Alzheimer’s disease”. Results: A total of 32 studies were analyzed, which indicated that curcumin supplementation reverses neurotoxic and behavioral damages in both in vivo and in vitro models of AD. Conclusion: The administration of curcumin in experimental models seems to be a promising approach in AD, even though it is suggested that additional studies must be conducted using distinct doses and through other routes of administration.

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

Current Drug Targets ◽

10.2174/1389450120666191017114735 ◽

2020 ◽

Vol 21 (5) ◽

pp. 433-444 ◽

Cited By ~ 1

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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Lysosomal Fusion Dysfunction as a Unifying Hypothesis for Alzheimer's Disease Pathology

International Journal of Alzheimer s Disease ◽

10.1155/2012/752894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Kristen E. Funk ◽

Jeff Kuret

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Neurofibrillary Tangles ◽

Recent Literature ◽

Senile Plaques ◽

Disease Onset ◽

Granulovacuolar Degeneration

Alzheimer's disease is characterized pathologically by extracellular senile plaques, intracellular neurofibrillary tangles, and granulovacuolar degeneration. It has been debated whether these hallmark lesions are markers or mediators of disease progression, and numerous paradigms have been proposed to explain the appearance of each lesion individually. However, the unfaltering predictability of these lesions suggests a single pathological nidus central to disease onset and progression. One of the earliest pathologies observed in Alzheimer's disease is endocytic dysfunction. Here we review the recent literature of endocytic dysfunction with particular focus on disrupted lysosomal fusion and propose it as a unifying hypothesis for the three most-studied lesions of Alzheimer's disease.

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Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?

Antioxidants ◽

10.3390/antiox10081257 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1257

Author(s):

Maria Assunta Potenza ◽

Luca Sgarra ◽

Vanessa Desantis ◽

Carmela Nacci ◽

Monica Montagnani

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Senile Plaques ◽

Mitochondrial Activity ◽

Enhanced Production ◽

The Common ◽

The Brain

A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.

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Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer’s Disease Development

Molecules ◽

10.3390/molecules26102897 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2897

Author(s):

Anatoly S. Urban ◽

Konstantin V. Pavlov ◽

Anna V. Kamynina ◽

Ivan S. Okhrimenko ◽

Alexander S. Arseniev ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Transmembrane Domain ◽

Senile Plaques ◽

Amyloid Β ◽

Conformational Behavior ◽

Amyloid Β Peptide ◽

Structural Studies ◽

Aβ Production

Alzheimer’s disease is the most common type of neurodegenerative disease in the world. Genetic evidence strongly suggests that aberrant generation, aggregation, and/or clearance of neurotoxic amyloid-β peptides (Aβ) triggers the disease. Aβ accumulates at the points of contact of neurons in ordered cords and fibrils, forming the so-called senile plaques. Aβ isoforms of different lengths are found in healthy human brains regardless of age and appear to play a role in signaling pathways in the brain and to have neuroprotective properties at low concentrations. In recent years, different substances have been developed targeting Aβ production, aggregation, interaction with other molecules, and clearance, including peptide-based drugs. Aβ is a product of sequential cleavage of the membrane glycoprotein APP (amyloid precursor protein) by β- and γ-secretases. A number of familial mutations causing an early onset of the disease have been identified in the APP, especially in its transmembrane domain. The mutations are reported to influence the production, oligomerization, and conformational behavior of Aβ peptides. This review highlights the results of structural studies of the main proteins involved in Alzheimer’s disease pathogenesis and the molecular mechanisms by which perspective therapeutic substances can affect Aβ production and nucleation.

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Systemic Actions of SGLT2 Inhibition on Chronic mTOR Activation as a Shared Pathogenic Mechanism between Alzheimer’s Disease and Diabetes

Biomedicines ◽

10.3390/biomedicines9050576 ◽

2021 ◽

Vol 9 (5) ◽

pp. 576

Author(s):

Gabriela Dumitrita Stanciu ◽

Razvan Nicolae Rusu ◽

Veronica Bild ◽

Leontina Elena Filipiuc ◽

Bogdan-Ionel Tamba ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Senile Plaques ◽

Unmet Need ◽

Pathogenic Mechanism ◽

Metabolic Dysfunction ◽

Sodium Glucose Cotransporter ◽

Sglt2 Inhibition ◽

Type 3

Alzheimer’s disease (AD) affects tens of millions of people worldwide. Despite the advances in understanding the disease, there is an increased urgency for pharmacological approaches able of impacting its onset and progression. With a multifactorial nature, high incidence and prevalence in later years of life, there is growing evidence highlighting a relationship between metabolic dysfunction related to diabetes and subject’s susceptibility to develop AD. The link seems so solid that sometimes AD and type 3 diabetes are used interchangeably. A candidate for a shared pathogenic mechanism linking these conditions is chronically-activated mechanistic target of rapamycin (mTOR). Chronic activation of unrestrained mTOR could be responsible for sustaining metabolic dysfunction that causes the breakdown of the blood-brain barrier, tau hyperphosphorylation and senile plaques formation in AD. It has been suggested that inhibition of sodium glucose cotransporter 2 (SGLT2) mediated by constant glucose loss, may restore mTOR cycle via nutrient-driven, preventing or even decreasing the AD progression. Currently, there is an unmet need for further research insight into molecular mechanisms that drive the onset and AD advancement as well as an increase in efforts to expand the testing of potential therapeutic strategies aimed to counteract disease progression in order to structure effective therapies.

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