Platelet Phosphorylated TDP-43: An Exploratory Study for a Peripheral Surrogate Biomarker Development for Alzheimer’s Disease

Wilhite, Rodger; Sage, Jessica; Bouzid, Abdurrahman; Primavera, Tyler; Agbaş, Abdulbakî

doi:10.4155/fsoa-2017-0090

Cited by 17 publications

(14 citation statements)

References 67 publications

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“…Some reports also recently discovered that platelets contain a proteolytic system by which hemostasis and thrombosis is acquired [17,18] . Since we have shown that an elevation of pathological pTDP43 within the platelet cytosol is correlated to hippocampal cortex of AD patients [13] , it was imperative that we analyze these platelet proteolytic systems. We attempted to establish any change of the protein concentrations of proteolytic system, since platelet proteasome concentrations have not been reported prior to our studies.…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated that a TAR-DNA/RNA binding protein (TDP-43) and its phosphorylated derivative (pTDP-43) levels were elevated in platelets obtained from AD patients as part of the blood-based biomarker development studies [13] . In this pilot study, we assessed the profile of target proteins for proteolytic machinery in platelet lysates obtained from AD patients and non-demented control subjects.…”

Section: Introductionmentioning

confidence: 99%

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Platelet proteolytic machinery assessment in Alzheimer’s disease

Muriu¹,

Sage²,

Agbaş³

2020

JUMD

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Aim: Platelets provide substantial information about the proteolytic system profile in neurodegenerative diseases. Assessment of autophagy and proteasome target proteins in platelets may reflect the tissue proteolytic machinery profile in the central nervous system of patients with Alzheimer's disease (AD). We aimed to demonstrate the optimum assay conditions and identify target proteins in platelet proteolytic machinery. Methods: Platelet samples were obtained from clinically verified AD patients and age-matched non-demented control subjects who were recruited by the University of Kansas Alzheimer's disease Center. Autophagosome participating proteins in platelets were identified by Western blotting analysis. Standard gel electrophoresis and electro transfer apparatus were used for protein transfer onto the membrane. Several antibodies were tested to identify the best working antibodies, and their concentrations were optimized. An enzyme-linked immunosorbent assay kit was used for platelet proteasome protein determination. Infrared imaging technology was used for visualizing the proteins on the membrane. Results: Autophagosome participating proteins showed elevated levels in AD patient platelet cytosol. Only light chain 3-1 autophagosome protein levels were significantly elevated. The concentrations of platelet lysate proteasome were assessed. AD patient's proteasome levels were elevated but they were statistically not different from controls. Conclusion: Platelets can be used for assessing whether the proteolytic system is functional. Blood-based sampling from human donors is less-invasive and analyzing the platelet proteolytic system profile may help to develop pharmaceutical intervention approaches for neurodegenerative diseases in general.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Platelet proteolytic machinery assessment in Alzheimer’s disease

Muriu¹,

Sage²,

Agbaş³

2020

JUMD

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“…Although it is clear that AD is a disease of synaptic failure, the exact mechanisms causing neuronal dysfunctions and survival involve multiple aspects and remain to be determined. While aggregated Aβ is regarded as a catastrophic factor in AD pathogenesis, altered functions related to apolipoprotein E4 (ApoE4) [45,46], tau [30,47], α-synuclein [48,49], and TDP-43 (transactive response DNA binding protein 43 kDa) [50][51][52] are likely comorbidity factors. Other pathological factors such as inflammatory response, ion homeostasis disruption, oxidative stress, and decreased levels of neurotransmitters have also been identified and are considered to be sequential events of Aβ aggregation [53][54][55][56].…”

Section: Mediated Aβ Reduction As An Alzheimer's Disease (Ad) Therapymentioning

confidence: 99%

A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment

2019

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Alzheimer's disease (AD), the most common cause of age-dependent dementia, is one of the most significant healthcare problems worldwide. Aggravating this situation, drugs that are currently US Food and Drug Administration (FDA)-approved for AD treatment do not prevent or delay disease progression. Therefore, developing effective therapies for AD patients is of critical urgency. Human genetic and clinical studies over the past three decades have indicated that abnormal generation or accumulation of amyloid-β (Aβ) peptides is a likely culprit in AD pathogenesis. Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1) (memapsin 2, β-secretase, Asp 2 protease) and γ-secretase. Mice deficient in BACE1 show abrogated production of Aβ. Therefore, pharmacological inhibition of BACE1 is being intensively pursued as a therapeutic approach to treat AD patients. Recent setbacks in clinical trials with BACE1 inhibitors have highlighted the critical importance of understanding how to properly inhibit BACE1 to treat AD patients. This review summarizes the recent studies on the role of BACE1 in synaptic functions as well as our views on BACE1 inhibition as an effective AD treatment.

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“…However, readers should be aware that there are some naturally occurring nonpathogenic amyloid-like fibril formations such as the nanostructure of certain bacteria [35] and the mammalian melanocyte integral membrane protein [36]. The pathogenesis of amyloidogenic proteinopathy may be initiated with amyloidogenic peptide fragments by one or more proteases [37]. Human amyloid pathologies known to require proteolytic processing of a precursor protein include AD where Aβ peptide fragments are liberated from a large APP precursor protein by β-and γsecretases [38].…”

Section: Proteolysis-generated Toxic Protein Speciesmentioning

confidence: 99%

“…The major representatives of such disorders are the amyloidoses, in which protein aggregation in the extracellular space is associated with the presence of malfunctioned protein molecules [37,90]. The chaperone-like small molecules may have the potential to be included in the treatment options for amyloidoses [91].…”

Section: Therapeutic Approach To Protein-misfolding Diseasementioning

confidence: 99%

Trends of Protein Aggregation in Neurodegenerative Diseases

Agbaş¹

2019

Neurochemical Basis of Brain Function and Dysfunction

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Protein aggregation trends in neurodegenerative diseases are largely unmapped due to the complex nature of protein-protein interactions and their regulatory machineries such as protein proteolytic systems. Since the protein aggregation process in humans is a slow process, early determination of the patients that will develop neurodegenerative diseases later in life is critical in terms of starting effective treatment, which will reduce the expensive health care. In this chapter, I will discuss the nature of protein aggregation of signature proteins and the status of protein proteolytic systems such as proteasome and autophagosome in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Huntington's disease, and prion disease under the light of recent studies including our new findings.

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Platelet Phosphorylated TDP-43: An Exploratory Study for a Peripheral Surrogate Biomarker Development for Alzheimer’s Disease

Cited by 17 publications

References 67 publications

Platelet proteolytic machinery assessment in Alzheimer’s disease

Platelet proteolytic machinery assessment in Alzheimer’s disease

A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment

Trends of Protein Aggregation in Neurodegenerative Diseases

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