Human Platelets Tau: A Potential Peripheral Marker for Alzheimer's Disease

Neumann, Karen F.; Farías, Gonzalo; Slachevsky, Andrea; Pérez, Patricio; Maccioni, Ricardo B.

doi:10.3233/jad-2011-101641

Cited by 84 publications

(64 citation statements)

References 26 publications

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“…The increased platelet GSK3β activity was reported in patients in early AD stages [29]. The definite role of platelet GSK3β is still unclear, but there is evidence of its involvement in the regulation of platelet activation and τ forms in AD [28][29][30]. The potential of molecular changes related to τ and amyloid pathology in platelets as diagnostic biomarkers is promising and awaits further investigation.…”

Section: Reviewmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Reviewmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…Li et al [42] first characterized the expression of the Tau protein in platelets, and further showed that the phosphoepitope thr-212 is dephosphorylated as a consequence of the inhibition of GSK3B in platelet homogenates. A recent study from Neumann et al [11] showed that several molecular species of Tau are present in platelets, and AD patients have a different proportion of the various forms of Tau as compared to controls. In fact they found several immunoreactive fractions ranging from approximately 60 to 240 kDa and, notably, that high molecular weight fractions of Tau (110-130 kDa) are increased in AD patients as compared with controls.…”

Section: Glycogen Synthase Kinase and Taumentioning

confidence: 99%

“…In addition, the ratio between high molecular weight and low molecular weight (ranging from 66 to 68 kDa) fractions seems to be significantly increased in AD subjects. The oligomers of the high molecular weight form of Tau may correspond to aggregates of the nearly 60 kDa monomer forms which subsequently decrease since they are consumed when higher order oligomers are being formed in AD [11] .…”

Section: Glycogen Synthase Kinase and Taumentioning

confidence: 99%

“…Studies have shown that platelets may be used as peripheral models for the analysis of metabolic pathways related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress. Platelets are the most important source of circulating forms of APP [5] and other important pathophysiological components of AD, such as microtubule-associated protein Tau [11] and glycogen synthase kinase-3B (GSK3B) [10] . In addition, platelets contain APP-cleaving enzymes, which are biologically active and responsive to systemic stimuli., Using platelets to address the systemic regulation of APP metabolism, offers many possibilities in the search for surrogate markers of intracerebral pathology and effects of pharmacological interventions.…”

Section: Topic Highlightmentioning

confidence: 99%

See 1 more Smart Citation

Platelet biomarkers in Alzheimer’s disease

Talib

Joaquim²,

Forlenza³

2012

WJP

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The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.

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“…Clinical studies are underway to validate PET images that differentiate stages of AD and controls. As a complementary approach, we have studied tau in cerebrospinal fluid (CSF) and also in peripheral blood platelets, providing promising biological non-invasive markers for AD Neumann et al, 2011).…”

Section: Integrated Efforts Toward Prevention Diagnosis and Treatmenmentioning

confidence: 99%