Hypothesis review: Alzheimer's overture guidelines

Brain Pathology, Год журнала: 2022, Номер 33(1)

Опубликована: Окт. 12, 2022

Abstract National Institute on Aging–Alzheimer's Association definition and classification of sporadic Alzheimer's disease (sAD) is based the assumption that β‐amyloid drives pathogenesis sAD, therefore, pathology sine‐qua‐non condition for diagnosis sAD. The neuropathological concurrence senile plaques (SPs) neurofibrillary tangles (NFTs) designated as changes. However, NFTs develop in brain decades before appearance SPs, their distribution does not parallel SPs. Moreover, are found about 85% individuals at age 65 around 97% 80. SPs occur 30% 50%–60% More than 70 genetic risk factors have been identified sAD; encoded proteins modulate cell membranes, synapses, lipid metabolism, neuroinflammation. (AD) overture provides a new concept aging sAD further discussion. AD proposes is: (i) multifactorial progressive neurodegenerative biological process, (ii) characterized by early 3R + 4Rtau NFTs, (iii) later deposition (iv) with particular non‐overlapped regional (v) preceded or occurring molecular changes affecting cytoskeleton, protein energy neuroinflammation, cycle, astrocytes, microglia, blood vessels; (vi) accompanied neuron loss atrophy, (vii) prevalent human aging, (viii) manifested pre‐clinical AD, progressing universally to mild cognitive impairment due mild, moderate, severe dementia.

Язык: Английский

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Controversial Past, Splendid Present, Unpredictable Future: A Brief Review of Alzheimer Disease History

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(2), С. 536 - 536

Опубликована: Янв. 17, 2024

Background: The concept of Alzheimer disease (AD)—since its histological discovery by to the present day—has undergone substantial modifications. Methods: We conducted a classical narrative review this field with bibliography selection (giving preference Medline best match). Results: following subjects are reviewed and discussed: Alzheimer’s discovery, Kraepelin’s creation new that was rare condition until 1970′s, growing interest investment in AD as major killer society large elderly population second half 20th century, consolidation clinicopathological model, modern nosology based on dominant amyloid hypothesis among many others. In 21st development biomarkers has supported novel biological definition AD, although proposed therapies have failed cure disease. incidence dementia/AD shown decrease affluent countries (possibly due control risk factors), mixed dementia been established most frequent etiology oldest old. Conclusions: current lacks unanimity. Many hypotheses attempt explain complex physiopathology entwined aging, cascade yielded poor therapeutic results. reduction appears promising but it should be confirmed future. A reevaluation is also necessary.

Язык: Английский

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A Scoping Review of Alzheimers Disease Hypotheses: An Array of Uni- and Multi-Factorial Theories

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 99(3), С. 843 - 856

Опубликована: Май 24, 2024

There is a common agreement that Alzheimers disease (AD) inherently complex; otherwise, general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed.

Язык: Английский

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Gut Microbiota and Alzheimer's Disease: Exploring Natural Product Intervention and the Gut–Brain Axis for Therapeutic Strategies

European Journal of Pharmacology, Год журнала: 2024, Номер unknown, С. 177022 - 177022

Опубликована: Окт. 1, 2024

Язык: Английский

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The unique neuropathological vulnerability of the human brain to aging

Ageing Research Reviews, Год журнала: 2023, Номер 87, С. 101916 - 101916

Опубликована: Март 28, 2023

Alzheimer's disease (AD)-related neurofibrillary tangles (NFT), argyrophilic grain (AGD), aging-related tau astrogliopathy (ARTAG), limbic predominant TDP-43 proteinopathy (LATE), and amygdala-predominant Lewy body (LBD) are proteinopathies that, together with hippocampal sclerosis, progressively appear in the elderly affecting from 50% to 99% of individuals aged 80 years, depending on disease. These disorders usually converge same subject associate additive cognitive impairment. Abnormal Tau, TDP-43, α-synuclein pathologies progress following a pattern consistent an active cell-to-cell transmission abnormal protein processing host cell. However, cell vulnerability pathways specific for each disorder, albeit proteins may co-localize particular neurons. All these alterations unique or highly prevalent humans. They all affect, at first, archicortex paleocortex extend later stages neocortex other regions telencephalon. observations show that phylogenetically oldest areas human cerebral cortex amygdala not designed cope lifespan actual New strategies aimed reducing functional overload telencephalon, including optimization dream repair mechanisms implementation artificial circuit devices surrogate brain functions, promising.

Язык: Английский

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Alzheimer’s Disease Neuropathological Change in Aged Non-Primate Mammals

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(15), С. 8118 - 8118

Опубликована: Июль 25, 2024

Human brain aging is characterized by the production and deposition of β-amyloid (Aβ) in form senile plaques cerebral amyloid angiopathy intracellular accumulation hyper-phosphorylated tau (Hp-tau) to neurofibrillary tangles (NFTs) dystrophic neurites plaques. The process progresses for years eventually manifests as cognitive impairment dementia a subgroup aged individuals. Aβ produced deposited first neocortex most mammals, including humans; it usually not accompanied altered behavior impairment. Hp-tau less frequent than pathology, NFTs are rare mammals. In contrast, familiar from middle age onward appear paleocortex selected stem nuclei. precede decades or correlate with about 5% individuals at 65 25% 85. Based on these comparative data, (a) common Alzheimer’s disease neuropathological change (ADNC) mammals; (b) common, however, principal cytoskeletal pathology (c) NFT humans starts nuclei paleocortical regions progressing parts other telencephalon; (d) human unique among mammalian species due early appearance dramatic progression onward, matching advanced cases; (e) neither nor supports concept cascade hypothesis.

Язык: Английский

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CRISPR/Cas9-Based therapeutics as a promising strategy for management of Alzheimer’s disease: progress and prospects

Frontiers in Cellular Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Апрель 7, 2025

CRISPR/Cas9 technology has revolutionized genetic and biomedical research in recent years. It enables editing modulation of gene function with an unparalleled precision effectiveness. Among the various applications prospects this technology, opportunities it offers unraveling molecular underpinnings a myriad central nervous system diseases, including neurodegenerative disorders, psychiatric conditions, developmental abnormalities, are unprecedented. In review, we highlight CRISPR/Cas9-based therapeutics as promising strategy for management Alzheimer's disease transformative impact on AD research. Further, emphasize role generating accurate models identification novel therapeutic targets, besides CRISPR-based therapies aimed at correcting AD-associated mutations modulating processes. Furthermore, delivery systems reviewed potential non-viral nanotechnology-based carriers overcoming critical limitations effective is discussed. Overall, review highlights promise intricate processes underlying development AD, discusses its limitations, ethical concerns several challenges efficient across BBB, ensuring specificity, avoiding off-target effects. This article can be helpful better understanding based approaches way forward utilizing enormous targeted, gene-specific treatments that could change trajectory debilitating incurable illness.

Язык: Английский

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Amyloid-β Pathology Is the Common Nominator Proteinopathy of the Primate Brain Aging

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 100(s1), С. S153 - S164

Опубликована: Июль 19, 2024

Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is common nominator proteinopathy primate aging. The abundance well tolerated, impact on cognitive functions usually limited particular tasks. In contrast, human characterized by early appearance HPtau pathology, forming neurofibrillary tangles, dystrophic neurites neuritic neuropil threads, preceding deposits several decades its severity progressing selected nuclei stem, entorhinal cortex, hippocampus limbic system, neocortex, other regions. Neurofibrillary tangles correlate with impairment dementia advanced cases. linked humans altered membrane protein lipid composition, particularly involving rafts. Although similar alterations unknown senescence postulated cause activated β-amyloidogenic pathway, prevailing signature

Язык: Английский

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Compensatory Mechanisms in Early Alzheimer’s Disease and Clinical Setting: The Need for Novel Neuropsychological Strategies

Journal of Alzheimer s Disease Reports, Год журнала: 2023, Номер 7(1), С. 513 - 525

Опубликована: Апрель 10, 2023

Despite advances in the detection of biomarkers and design drugs that can slow progression Alzheimer’s disease (AD), underlying primary mechanisms have not been elucidated. The diagnosis AD has notably improved with development neuroimaging techniques cerebrospinal fluid which provided new information available past. Although advanced, there is a consensus among experts that, when making specific patient, many years probably passed since onset processes, it very likely use their cutoffs do reflect true critical points for establishing precise stage ongoing disease. In this context, frequent disparities between current cognitive functional performance clinical practice constitute major drawback translational neurology. To our knowledge, In-Out-test only neuropsychological test developed idea compensatory brain exist early stages AD, whose positive effects on conventional tests be reduced assessing episodic memory context dual-task, through executive auxiliary networks are ‘distracted’, thus uncover real deficit. Furthermore, as additional traits, age formal education no impact In-Out-test.

Язык: Английский

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Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes

Aging, Год журнала: 2023, Номер 15(9), С. 3295 - 3330

Опубликована: Май 13, 2023

(Phospho)proteomics of old-aged subjects without cognitive or behavioral symptoms, and AD-neuropathological changes lacking any other neurodegenerative alteration will increase understanding about the physiological state human brain aging associate neurological deficits neuropathological lesions.(Phospho)proteomics using conventional label-free- SWATH-MS (Sequential window acquisition all theoretical fragment ion spectra mass spectrometry) has been assessed in frontal cortex (FC) individuals NFTs, senile plaques (SPs) age-related co-morbidities classified by age (years) four groups; group 1 (young, 30-44); 2 (middle-aged: MA, 45-52); 3 (early-elderly, 64-70); 4 (late-elderly, 75-85).Protein levels deregulated protein phosphorylation linked to similar biological terms/functions, but involving different individual proteins, are found FC with age. The modified expression occurs cytoskeleton membranes, synapses, vesicles, myelin, membrane transport channels, DNA RNA metabolism, ubiquitin-proteasome-system (UPS), kinases phosphatases, fatty acid mitochondria. Dysregulated phosphoproteins associated cytoskeleton, including microfilaments, actin-binding intermediate filaments neurons glial cells, microtubules; dense core vesicles; phosphatases; proteins RNA; members UPS; GTPase regulation; inflammation; lipid metabolism. Noteworthy, large clusters hierarchically-related stable until 70. However, components cell vesicles modulation, cellular structures (including tau tubulin filaments) markedly altered from 75. Similarly, marked modifications occur larger phosphoprotein neuronal structures, stabilization, kinase regulation late elderly.Present findings may proteostasis elderly subpopulation not having AD change telencephalon region.

Язык: Английский

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