scholarly journals Molecular Imaging of Fluorinated Probes for Tau Protein and Amyloid-β Detection

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3413 ◽  
Author(s):  
Sarah K. Yeo ◽  
Yurii Shepelytskyi ◽  
Vira Grynko ◽  
Mitchell S. Albert
Keyword(s):  
Molecular Imaging ◽  
Tau Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Molecular Probes ◽  
Definitive Diagnosis ◽  
Public Health Issue ◽  
Major Public Health Issue ◽  
Hyperphosphorylated Tau Protein ◽  
Progressive Neurodegeneration

Alzheimer’s disease (AD) is the most common form of dementia and results in progressive neurodegeneration. The incidence rate of AD is increasing, creating a major public health issue. AD is characterized by neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and senile plaques composed of amyloid-β (Aβ). Currently, a definitive diagnosis of AD is accomplished post-mortem. Thus, the use of molecular probes that are able to selectively bind to NFTs or Aβ can be valuable tools for the accurate and early diagnosis of AD. The aim of this review is to summarize and highlight fluorinated molecular probes that can be used for molecular imaging to detect either NFTs or Aβ. Specifically, fluorinated molecular probes used in conjunction with 19F MRI, PET, and fluorescence imaging will be explored.

scholarly journals Neuronal Deposition of Amyloid-β Oligomers and Hyperphosphorylated Tau Is Closely Connected with Cognitive Dysfunction in Aged Dogs

2021 ◽  
pp. 1-12
Author(s):  
Umma Habiba ◽  
Makiko Ozawa ◽  
James K. Chambers ◽  
Kazuyuki Uchida ◽  
Joseph Descallar ◽  
...  
Keyword(s):  
Cognitive Dysfunction ◽  
Tau Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Hyperphosphorylated Tau ◽  
Diffuse Type ◽  
Hippocampal Region ◽  
Immunofluorescence Analysis ◽  
Relevant Model ◽  
Hyperphosphorylated Tau Protein

Background: Canine cognitive dysfunction (CCD) is a progressive syndrome recognized in mature to aged dogs with a variety of neuropathological changes similar to human Alzheimer’s disease (AD), for which it is thought to be a good natural model. However, the presence of hyperphosphorylated tau protein (p-Tau) in dogs with CCD has only been demonstrated infrequently. Objective: The aim of the present study was to investigate the presence of p-Tau and amyloid-β oligomer (Aβo) in cerebral cortex and hippocampus of dogs with CCD, with focus on an epitope retrieval protocol to unmask p-Tau. Methods: Immunohistochemical and immunofluorescence analysis of the cortical and hippocampal regions of five CCD-affected and two nondemented aged dogs using 4G8 anti-Aβp, anti-Aβ 1 - 42 nanobody (PrioAD13) and AT8 anti-p-Tau (Ser202, Thr205) antibody were used to demonstrate the presence of Aβ plaques (Aβp) and Aβ 1 - 42 oligomers and p-Tau deposits, respectively. Results: The extracellular Aβ senile plaques were of the diffuse type which lack the dense core normally seen in human AD. While p-Tau deposits displayed a widespread pattern and closely resembled the typical human neuropathology, they did not co-localize with the Aβp. Of considerable interest, however, widespread intraneuronal deposition of Aβ 1 - 42 oligomers were exhibited in the frontal cortex and hippocampal region that co-localized with p-Tau. Conclusion: Taken together, these findings reveal further shared neuropathologic features of AD and CCD, supporting the case that aged dogs afflicted with CCD offer a relevant model for investigating human AD.

scholarly journals Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1261
Author(s):  
Laura D’Andrea ◽  
Ramona Stringhi ◽  
Monica Di Luca ◽  
Elena Marcello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Hyperphosphorylated Tau Protein ◽  
Ε4 Allele ◽  
Therapeutic Tools

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.

scholarly journals Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target?

2019 ◽  
Vol 20 (3) ◽  
pp. 558 ◽  
Author(s):  
Yuan Dong ◽  
Xiaoheng Li ◽  
Jinbo Cheng ◽  
Lin Hou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Tau Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Cognitive Changes ◽  
Hyperphosphorylated Tau Protein ◽  
Common Causes ◽  
The Brain

Alzheimer’s disease (AD) is one of the most common causes of dementia. Its pathogenesis is characterized by the aggregation of the amyloid-β (Aβ) protein in senile plaques and the hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Current medications for AD can provide temporary help with the memory symptoms and other cognitive changes of patients, however, they are not able to stop or reverse the progression of AD. New medication discovery and the development of a cure for AD is urgently in need. In this review, we summarized drugs for AD treatments and their recent updates, and discussed the potential of microglia induced neuroinflammation as a target for anti-AD drug development.

scholarly journals Alzheimer’s disease as an inflammatory disease

2017 ◽  
Vol 8 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Marta Bolós ◽  
Juan Ramón Perea ◽  
Jesús Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Short Review ◽  
Hyperphosphorylated Tau ◽  
Progressive Dementia ◽  
Hyperphosphorylated Tau Protein

AbstractAlzheimer’s disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leading to progressive dementia. In this short review, we focus on neuroinflammation in AD. Specifically, we describe the participation of microglia, as well as other factors that may contribute to inflammation, in neurodegeneration.

scholarly journals Neuronal Trafficking of the Amyloid Precursor Protein—What Do We Really Know?

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 801
Author(s):  
Tong Lin ◽  
Lars O. Tjernberg ◽  
Sophia Schedin-Weiss
Keyword(s):  
Complex Disease ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Lipoprotein Receptors ◽  
Hyperphosphorylated Tau Protein ◽  
Intracellular Compartments ◽  
Neuronal Transport

Alzheimer’s disease (AD) is the most common type of dementia, contributing to 60–80% of cases. It is a neurodegenerative disease that usually starts symptomless in the first two to three decades and then propagates into a long-term, irreversible disease, resulting in the progressive loss of memory, reasoning, abstraction and language capabilities. It is a complex disease, involving a large number of entangled players, and there is no effective treatment to cure it or alter its progressive course. Therefore, a thorough understanding of the disease pathology and an early diagnosis are both necessary. AD has two significant pathological hallmarks: extracellular senile plaques composed of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and the aggregation of Aβ, which starts in earlier stages, is usually claimed to be the primary cause of AD. Secretases that cleave Aβ precursor protein (APP) and produce neurotoxic Aβ reside in distinct organelles of the cell, and current concepts suggest that APP moves between distinct intracellular compartments. Obviously, APP transport and processing are intimately related processes that cannot be dissociated from each other, and, thus, how and where APP is transported determines its processing fate. In this review, we summarize critical mechanisms underlying neuronal APP transport, which we divide into separate parts: (1) secretory pathways and (2) endocytic and autophagic pathways. We also include two lipoprotein receptors that play essential roles in APP transport: sorting-related receptor with A-type repeats and sortilin. Moreover, we consider here some major disruptions in the neuronal transport of APP that contribute to AD physiology and pathology. Lastly, we discuss current methods and technical difficulties in the studies of APP transport.

scholarly journals Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Viktoriya Zhuravleva ◽  
João Vaz-Silva ◽  
Mei Zhu ◽  
Patricia Gomes ◽  
Joana M. Silva ◽  
...  
Keyword(s):  
Tau Protein ◽  
Intracellular Trafficking ◽  
Stress Hormones ◽  
Amyloid Β ◽  
Small Gtpase ◽  
Aβ Peptides ◽  
App Processing ◽  
Hyperphosphorylated Tau Protein ◽  
Open Question ◽  
Aβ Production

AbstractChronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer’s disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, we show that Rab35 negatively regulates Aβ production by sorting amyloid precursor protein (APP) and β-secretase (BACE1) out of the endosomal network, where they interact to produce Aβ. Interestingly, Rab35 coordinates distinct intracellular trafficking steps for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we demonstrate that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress-related and AD-related amyloidogenesis.

scholarly journals Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production

2021 ◽  
Author(s):  
Viktoriya Zhuravleva ◽  
João Vaz Silva ◽  
Mei Zhu ◽  
Patrícia Gomes ◽  
Joana M Silva ◽  
...  
Keyword(s):  
Tau Protein ◽  
Intracellular Trafficking ◽  
Stress Hormones ◽  
Amyloid Β ◽  
Small Gtpase ◽  
Aβ Peptides ◽  
App Processing ◽  
Hyperphosphorylated Tau Protein ◽  
Open Question ◽  
Aβ Production

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer's disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, Rab35 negatively regulates Aβ production by sorting amyloid precursor protein (APP) and β-secretase (BACE1) out of the endosomal network, where they interact to produce Aβ. Interestingly, Rab35 coordinates distinct intracellular trafficking events for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we show that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress- and AD-related amyloidogenesis.

The Implications of Autophagy in Alzheimer’s Disease

2018 ◽  
Vol 15 (14) ◽  
pp. 1283-1296 ◽  
Author(s):  
Tadanori Hamano ◽  
Kouji Hayashi ◽  
Norimichi Shirafuji ◽  
Yasunari Nakamoto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Tau Protein ◽  
Protective Factor ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Model Studies ◽  
Β Protein

The pathogenic mechanisms of Alzheimer’s Disease (AD) involve the deposition of abnormally misfolded proteins, amyloid β protein (Aβ) and tau protein. Aβ comprises senile plaques, and tau aggregates form Neurofibrillary Tangles (NFTs), both of which are hallmarks of AD. Autophagy is the main conserved pathway for the degeneration of aggregated proteins, Aβ, tau and dysfunctional organelles in the cell. Many animal model studies have demonstrated that autophagy normally functions as the protective factor against AD progression associated with intracytoplasmic toxic Aβ and tau aggregates. The upregulation of autophagy can also be favorable in AD treatment. An improved understanding of the signaling pathways that regulate autophagy is critical to developing AD treatments. The cellular and molecular machineries of autophagy, their function in the pathogenesis of AD, and current drug discovery strategies will be discussed in this review.

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