Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

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RNA and Oxidative Stress in Alzheimer’s Disease: Focus on microRNAs

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/2638130 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Akihiko Nunomura ◽

George Perry

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Early Stage ◽

Brain Regions ◽

Prodromal Stage ◽

Adaptive Mechanisms ◽

Therapeutic Tools ◽

Key Events

Oxidative stress (OS) is one of the major pathomechanisms of Alzheimer’s disease (AD), which is closely associated with other key events in neurodegeneration such as mitochondrial dysfunction, inflammation, metal dysregulation, and protein misfolding. Oxidized RNAs are identified in brains of AD patients at the prodromal stage. Indeed, oxidized mRNA, rRNA, and tRNA lead to retarded or aberrant protein synthesis. OS interferes with not only these translational machineries but also regulatory mechanisms of noncoding RNAs, especially microRNAs (miRNAs). MiRNAs can be oxidized, which causes misrecognizing target mRNAs. Moreover, OS affects the expression of multiple miRNAs, and conversely, miRNAs regulate many genes involved in the OS response. Intriguingly, several miRNAs embedded in upstream regulators or downstream targets of OS are involved also in neurodegenerative pathways in AD. Specifically, seven upregulated miRNAs (miR-125b, miR-146a, miR-200c, miR-26b, miR-30e, miR-34a, miR-34c) and three downregulated miRNAs (miR-107, miR-210, miR-485), all of which are associated with OS, are found in vulnerable brain regions of AD at the prodromal stage. Growing evidence suggests that altered miRNAs may serve as targets for developing diagnostic or therapeutic tools for early-stage AD. Focusing on a neuroprotective transcriptional repressor, REST, and the concept of hormesis that are relevant to the OS response may provide clues to help us understand the role of the miRNA system in cellular and organismal adaptive mechanisms to OS.

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Platelet phosphorylated TDP-43: An exploratory study for a peripheral surrogate biomarker development for Alzheimer’s disease

10.1101/132837 ◽

2017 ◽

Author(s):

Rodger Wilhite ◽

Jessica Sage ◽

Abdurrahman Bouzid ◽

Tyler Primavera ◽

Abdulbaki Agbas

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Clinical Signs ◽

Brain Regions ◽

Post Mortem ◽

Disease Prognosis ◽

Post Mortem Brain ◽

And Control ◽

Lateral Sclerosis

AbstractAim: Alzheimer’s disease (AD) and other forms of dementia create a non-curable disease population in World’s societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & Methods: TDP-43 levels were analyzed in post-mortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in post-mortem AD brain regions and similar trends were also observed in patient’s platelets. Conclusion: Platelet TDP-43 could be used as a surrogate biomarker that is measurable, reproducible, and sensitive for screening the patients with some early clinical signs of AD and can be used to monitor disease prognosis.Lay abstractIn this study, we explore to identify an Alzheimer’s disease-selective phospho-specific antibody that recognizes the diseased form of TDP-43 protein in patient’s blood-derived platelets. Our results suggest that selective anti-phosphorylated TDP-43 antibody discriminates Alzheimer’s disease from non-demented controls and patients with amyotrophic lateral sclerosis. Therefore, platelet screening with a selective antibody could potentially be a useful tool for diagnostic purposes for Alzheimer’s disease.

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A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0823-2 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Ebru Ercan-Herbst ◽

Jens Ehrig ◽

David C. Schöndorf ◽

Annika Behrendt ◽

Bernd Klaus ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Temporal Cortex ◽

Brain Regions ◽

Phosphorylation Sites ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Small Set ◽

Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0–I, II or III–IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III–IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

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Early Detection of Alzheimer’s Disease: Detecting Asymmetries with a Return Random Walk Link Predictor

Entropy ◽

10.3390/e22040465 ◽

2020 ◽

Vol 22 (4) ◽

pp. 465

Author(s):

Manuel Curado ◽

Francisco Escolano ◽

Miguel A. Lozano ◽

Edwin R. Hancock

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Random Walk ◽

Early Stage ◽

Directed Graphs ◽

Brain Regions ◽

Functional Magnetic Resonance ◽

Left And Right ◽

The Brain ◽

Analyze Data

Alzheimer’s disease has been extensively studied using undirected graphs to represent the correlations of BOLD signals in different anatomical regions through functional magnetic resonance imaging (fMRI). However, there has been relatively little analysis of this kind of data using directed graphs, which potentially offer the potential to capture asymmetries in the interactions between different anatomical brain regions. The detection of these asymmetries is relevant to detect the disease in an early stage. For this reason, in this paper, we analyze data extracted from fMRI images using the net4Lap algorithm to infer a directed graph from the available BOLD signals, and then seek to determine asymmetries between the left and right hemispheres of the brain using a directed version of the Return Random Walk (RRW). Experimental evaluation of this method reveals that it leads to the identification of anatomical brain regions known to be implicated in the early development of Alzheimer’s disease in clinical studies.

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Neuropathology of Aging in Cats and its Similarities to Human Alzheimer’s Disease

Frontiers in Aging ◽

10.3389/fragi.2021.684607 ◽

2021 ◽

Vol 2 ◽

Author(s):

Lorena Sordo ◽

Alessandra C. Martini ◽

E. Fiona Houston ◽

Elizabeth Head ◽

Danièlle Gunn-Moore

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Senile Plaques ◽

Brain Regions ◽

Hyperphosphorylated Tau ◽

Age Related ◽

Cat Brain ◽

Amyloid Aβ ◽

Intraneuronal Aβ

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

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Network-level permutation entropy of resting-state MEG recordings: a novel biomarker for early-stage Alzheimer’s disease?

Network Neuroscience ◽

10.1162/netn_a_00224 ◽

2021 ◽

pp. 1-44

Author(s):

Elliz P. Scheijbeler ◽

Anne M. van Nifterick ◽

Cornelis J. Stam ◽

Arjan Hillebrand ◽

Alida A. Gouw ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Resting State ◽

Early Stage ◽

Brain Regions ◽

Permutation Entropy ◽

Subjective Cognitive Decline ◽

Local Activity ◽

Theta Power ◽

Potential Biomarker

Abstract Objective. Increasing evidence suggests that measures of signal variability and complexity could present promising biomarkers for Alzheimer’s disease (AD). Earlier studies have however been limited to the characterization of local activity. Here, we investigate whether a network version of permutation entropy could serve as a novel biomarker for early-stage AD. Methods. Resting-state source-space magnetoencephalography was recorded in 18 subjects with subjective cognitive decline (‘SCD’) and 18 subjects with mild cognitive impairment (‘MCI’). Local activity was characterized by permutation entropy (PE). Network interactions were studied using the inverted Joint Permutation Entropy (JPEinv), corrected for volume conduction. Results. The JPEinv showed a reduction of nonlinear connectivity in MCI subjects in the theta and alpha band. Local PE showed increased theta-band entropy. Between-group differences were widespread across brain regions. ROC analysis of classification of MCI versus SCD subjects revealed that a linear regression model trained on JPEinv features (78.4% [62.5–93.3%]) slightly outperformed PE (76.9% [60.3–93.4%]) and relative theta power based models (76.9% [60.4–93.3%]). Conclusion. Classification performance of theta JPEinv was at least as good as the relative theta power benchmark. The JPEinv is therefore a potential biomarker for early-stage AD, and should be explored in larger studies.

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A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

10.1101/594820 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ebru Ercan-Herbst ◽

David C. Schöndorf ◽

Annika Behrendt ◽

Bernd Klaus ◽

Borja Gomez Ramos ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Temporal Cortex ◽

Brain Regions ◽

Phosphorylation Sites ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Small Set ◽

Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0-I, II or III-IV, respectively, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We find that soluble tau oligomers are strongly increased at Braak stages III-IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau oligomerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble oligomers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs and shed light on early PTM changes of tau during AD pathogenesis in human brains.

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