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International Journal of Nanomedicine 2019Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of... (Review)
Review
Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of the major causative factors to induce progressive dementia. AD is a neurodegenerative disease, and its pathogenesis has been attributed to extracellular aggregates of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles made of hyperphosphorylated τ-protein in cortical and limbic areas of the human brain. It is characterized by memory loss and progressive neurocognitive dysfunction. The anomalous processing of APP by β-secretases and γ-secretases leads to production of Aβ and Aβ monomers, which further oligomerize and aggregate into senile plaques. The disease also intensifies through infectious agents like HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aβ peptides in central nervous system initiates microglial infiltration. Upon coming into vicinity of Aβ, microglia get activated, endocytose Aβ, and contribute toward their clearance via TREM2 surface receptors, simultaneously triggering innate immunoresponse against the aggregation. In addition to a detailed report on causative factors leading to AD, the present review also discusses the current state of the art in AD therapeutics and diagnostics, including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology as an efficient therapeutic strategy to increase the bioavailability of drugs in the central nervous system.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Epigenesis, Genetic; Humans; Nanotechnology; Plaque, Amyloid
PubMed: 31410002
DOI: 10.2147/IJN.S200490 -
Physiological Reviews Jul 2021The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and... (Review)
Review
The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and genetic subtypes and to formulate the first pathogenic hypothesis. Thanks to biomarkers and new technologies, the concept of AD then rapidly changed from a static view of an amnestic dementia of the presenium to a biological entity that could be clinically manifested as normal cognition or dementia of different types. What is clearly emerging from studies is that AD is heterogeneous in each aspect, such as amyloid composition, tau distribution, relation between amyloid and tau, clinical symptoms, and genetic background, and thus it is probably impossible to explain AD with a single pathological process. The scientific approach to AD suffers from chronological mismatches between clinical, pathological, and technological data, causing difficulty in conceiving diagnostic gold standards and in creating models for drug discovery and screening. A recent mathematical computer-based approach offers the opportunity to study AD in real life and to provide a new point of view and the final missing pieces of the AD puzzle.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Humans; Peptide Fragments; Plaque, Amyloid
PubMed: 33475022
DOI: 10.1152/physrev.00015.2020 -
Nature Reviews. Neurology Jan 2020The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between... (Review)
Review
The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Cerebral Amyloid Angiopathy; Humans; Plaque, Amyloid; Signal Transduction
PubMed: 31827267
DOI: 10.1038/s41582-019-0281-2 -
Folia Neuropathologica 2009Since the earliest descriptions of the disease, senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the pathological 'hallmarks' of Alzheimer's... (Review)
Review
Since the earliest descriptions of the disease, senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the pathological 'hallmarks' of Alzheimer's disease (AD). Whether or not SP and NFT are sufficient cause to explain the neurodegeneration of AD is controversial. The major molecular constituents of these lesions, viz., beta-amyloid (Ass) and tau, have played a defining role both in the diagnosis of the disease and in studies of pathogenesis. The molecular biology of SP and NFT, however, is complex with many chemical constituents. An individual constituent could be the residue of a pathogenic gene mutation, result from cellular degeneration, or reflect the acquisition of new proteins by diffusion and molecular binding. This review proposes that the molecular composition of SP and NFT is largely a consequence of cell degeneration and the later acquisition of proteins. Such a conclusion has implications both for the diagnosis of AD and in studies of disease pathogenesis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Neurofibrillary Tangles; Plaque, Amyloid; tau Proteins
PubMed: 20054780
DOI: No ID Found -
Neurotherapeutics : the Journal of the... Jan 2015Many lines of evidence support that β-amyloid (Aβ) peptides play an important role in Alzheimer's disease (AD), the most common cause of dementia. But despite much... (Review)
Review
Many lines of evidence support that β-amyloid (Aβ) peptides play an important role in Alzheimer's disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how Aβ contributes to AD remain unclear. While Aβ is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in Aβ has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting Aβ have not shown the hoped-for benefits. Thus, doubts have been growing about the role of Aβ as a therapeutic target. Here we review evidence supporting the involvement of Aβ in AD, highlight the importance of differentiating between various forms of Aβ, and suggest that a better understanding of Aβ's precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Humans; Plaque, Amyloid
PubMed: 25371168
DOI: 10.1007/s13311-014-0313-y -
Nature Reviews. Molecular Cell Biology Dec 2018The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and... (Review)
Review
The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.
Topics: Alzheimer Disease; Amyloid; Amyloidosis; Diabetes Mellitus, Type 2; Humans; Parkinson Disease; Plaque, Amyloid
PubMed: 30237470
DOI: 10.1038/s41580-018-0060-8 -
Journal of Diabetes Investigation Jan 2022The etiology of type 2 diabetes is multifactorial, in which environmental and genetic factors are involved to varying degrees. This suggests that its pathophysiology... (Review)
Review
The etiology of type 2 diabetes is multifactorial, in which environmental and genetic factors are involved to varying degrees. This suggests that its pathophysiology might vary depending on the individuals. Knowledge of the differences is critical, because these differences are directly linked to the care and treatment of the patients. Recent studies have attempted to carry out subclassifications of type 2 diabetes based on clinical and genetic differences. However, there is no pathological evidence to support these subclassifications. The pathophysiology of type 2 diabetes is generally divided into insulin resistance in peripheral tissues and pancreatic islet dysfunction. Among them, islet dysfunction causes a deficit in insulin secretion from β-cells. In particular, a deficit in insulin secretion is ascribed to a combination of disruption of the insulin secretory machinery and a decrease in β-cell volume in type 2 diabetes. Recent research has suggested that transdifferentiation and dedifferentiation are involved in the decrease in β-cell volume, and that it might change dynamically depending on the glucose metabolic state. However, it is possible that the numbers of islet cells are decreased in type 2 diabetes. In particular, the loss of endocrine cells due to islet amyloid deposits is an important pathological change in type 2 diabetes in humans. These results show that pathological changes of the islets can be different in each individuals with type 2 diabetes and reflect each pathophysiology, which is useful in establishing further subclassifications and developing tailor-made therapies for type 2 diabetes.
Topics: Aged, 80 and over; Amyloid; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Plaque, Amyloid
PubMed: 34562302
DOI: 10.1111/jdi.13679 -
Alzheimer's & Dementia : the Journal of... Jan 2015Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent...
Although amyloid imaging with PiB-PET ([C-11]Pittsburgh Compound-B positron emission tomography), and now with F-18-labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤ 45 years) and typical Alzheimer's disease patients. The units of this scale have been named "Centiloids." Basically, we describe a "standard" method of analyzing PiB PET data and then a method for scaling any "nonstandard" method of PiB PET analysis (or any other tracer) to the Centiloid scale.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Calibration; Fluorodeoxyglucose F18; Humans; Image Interpretation, Computer-Assisted; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles
PubMed: 25443857
DOI: 10.1016/j.jalz.2014.07.003 -
Nature Cell Biology Jul 2023Dysfunctional autophagy has been implicated in the pathogenesis of Alzheimer's disease (AD). Previous evidence suggested disruptions of multiple stages of the...
Dysfunctional autophagy has been implicated in the pathogenesis of Alzheimer's disease (AD). Previous evidence suggested disruptions of multiple stages of the autophagy-lysosomal pathway in affected neurons. However, whether and how deregulated autophagy in microglia, a cell type with an important link to AD, contributes to AD progression remains elusive. Here we report that autophagy is activated in microglia, particularly of disease-associated microglia surrounding amyloid plaques in AD mouse models. Inhibition of microglial autophagy causes disengagement of microglia from amyloid plaques, suppression of disease-associated microglia, and aggravation of neuropathology in AD mice. Mechanistically, autophagy deficiency promotes senescence-associated microglia as evidenced by reduced proliferation, increased Cdkn1a/p21, dystrophic morphologies and senescence-associated secretory phenotype. Pharmacological treatment removes autophagy-deficient senescent microglia and alleviates neuropathology in AD mice. Our study demonstrates the protective role of microglial autophagy in regulating the homeostasis of amyloid plaques and preventing senescence; removal of senescent microglia is a promising therapeutic strategy.
Topics: Mice; Animals; Microglia; Plaque, Amyloid; Alzheimer Disease; Autophagy; Neurons; Mice, Transgenic; Disease Models, Animal
PubMed: 37231161
DOI: 10.1038/s41556-023-01158-0 -
Acta Neuropathologica Dec 2014We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy...
We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
Topics: Aging; Brain; Diagnosis, Differential; Humans; Plaque, Amyloid; Tauopathies; Terminology as Topic
PubMed: 25348064
DOI: 10.1007/s00401-014-1349-0