Neuronal Neurofibrillary Tangles Research Articles

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment. Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD. A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded. Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO). The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.

Mirror-Image Phage Display for the Selection of D-Amino Acid Peptide Ligands as Potential Therapeutics.

In neurodegenerative diseases like Alzheimer's disease (AD), endogenous proteins or peptides aggregate with themselves. These proteins may lose their function or aggregates and/or oligomers can obtain toxicity, causing injury or death to cells. Aggregation of two major proteins characterizes AD. Amyloid-β peptide (Aβ) is deposited in amyloid plaques within the extracellular space of the brain and Tau in so-called neurofibrillary tangles in neurons. Finding peptide ligands to halt protein aggregation is a promising therapeutical approach. Using mirror-image phage display with a commercially available, randomized 12-mer peptide library, we have selected D-amino acid peptides, which bind to the Tau protein and modulate its aggregation in vitro. Peptides can bind specifically and selectively to a target molecule, but natural L-amino acid peptides may have crucial disadvantages for in vivo applications, as they are sensitive to protease degradation and may elicit immune responses. One strategy to circumvent these disadvantages is the use of non-naturally occurring D-amino acid peptides as they exhibit increased protease resistance and generally do not activate the immune system. To perform mirror-image phage display, the target protein needs to be synthesized as D-amino acid version. If the target protein sequence is too long to be synthesized properly, smaller peptides derived from the full length protein can be used for the selection process. This also offers the possibility to influence the binding region of the selected D-peptides in the full-length target protein. Here we provide the protocols for mirror-image phage display selection on the PHF6* peptide of Tau, based on the commercially available Ph.D.™-12 Phage Display Peptide Library Kit, leading to D-peptides that also bind the full length Tau protein (Tau441), next to PHF6*. In addition, we provide protocols and data for the first characterization of those D-peptides that inhibit Tau aggregation in vitro. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Mirror image phage display selection against D-PHF6* fibrils Support Protocol 1: Single phage ELISA Basic Protocol 2: Sequencing and D-peptide generation Basic Protocol 3: Thioflavin-T (ThT) test to control inhibition of Tau aggregation Support Protocol 2: Purification of full-length Tau protein Basic Protocol 4: ELISA to demonstrate the binding of the generated D-peptides to PHF6* and full-length Tau fibrils.

A new metal ion chelator attenuates human tau accumulation-induced neurodegeneration and memory deficits in mice

Neuronal neurofibrillary tangles containing Tau hyperphosphorylation proteins are a typical pathological marker of Alzheimer's disease (AD). The level of tangles in neurons correlates positively with severe dementia. However, how Tau induces cognitive dysfunction is still unknown, which leads to a lack of effective treatments for AD. Metal ions deposition occurs with tangles in AD brain autopsy. Reduced metal ion can improve the pathology of AD. To explore whether abnormally phosphorylated Tau causes metal ion deposition, we overexpressed human full-length Tau (hTau) in the hippocampal CA3 area of mice and primary cultured hippocampal neurons (CPHN) and found that Tau accumulation induced iron deposition and activated calcineurin (CaN), which dephosphorylates glycogen synthase kinase 3 beta (GSK3β), mediating Tau hyperphosphorylation. Simultaneous activation of CaN dephosphorylates cyclic-AMP response binding protein (CREB), leading to synaptic deficits and memory impairment, as shown in our previous study; this seems to be a vicious cycle exacerbating tauopathy. In the current study, we developed a new metal ion chelator that displayed a significant inhibitory effect on Tau phosphorylation and memory impairment by chelating iron ions in vivo and in vitro. These findings provide new insight into the mechanism of memory impairment induced by Tau accumulation and develop a novel potential treatment for tauopathy in AD.

Investigating the role of structural variants in Alzheimer’s Disease and AD‐Related traits

AbstractBackgroundAlthough recent advances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD), there remains a discrepancy between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.MethodHere, we investigate the role of SVs in AD and AD‐related dementias (ADRD) by leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). We analyzed over 25,000 SVs discovered using whole genome sequencing (WGS) data of 1,106 participants and tested for association with multiple indices for AD/ADRD, including measurements of cognitive decline, amyloid beta, neuronal neurofibrillary tangles, TDP‐43, cerebral amyloid angiopathy, and resilience.ResultOur findings revealed five associations reaching genome‐wide significance. These included a 106 bp insertion (chr21:17,134,448; MAF = 0.01), located in the intronic region of the gene USP25, associated with a higher TDP‐43 burden (P‐value = 1.83×10−6). An 82 bp insertion at chr19:45,444,699 (MAF = 0.25), previously mapped as eQTL for APOC1 and sQTL for APOC2 in brain tissues, was linked to greater cerebral amyloid angiopathy (P‐value = 1.02×10−6). An 820 bp deletion chr15:26,003,040 (MAF = 0.031) overlapping a CTCF site near ATP10A was associated with greater odds of Lewy Body disease (P‐value = 1.03×10−6). A 55 bp insertion (chr12:131,797,376; MAF = 0.21) in an intergenic region was found to be associated with reduced vascular disease burden (P‐value = 2.96×10−7); and a 53 bp insertion (chr4:99,901,557; MAF = 0.014) mapped as protein QTL for ADH5 was linked to lower cognitive resilience (P‐value = 8.51×10−7).ConclusionThese findings provide evidence that common genetic variation, particularly SVs, can play a significant role in AD/ADRD traits. We are now investigating the functional impact of these SVs by integrating multi‐omics assays available from brain tissues of the same individuals. Our goal is to connect genetics to phenotype and gain a deeper understanding of the role of SVs in AD/ADRD.

Newly identified transmembrane protein 106B amyloid fibrils in the human brain: pathogens or by-products?

Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) constitute a spectrum of diseases characterized by the abnormal aggregation of specific amyloid fibrillar proteins; these include β-amyloid (Aβ) and tau in the form of the extracellular Aβ plaques and neuronal neurofibrillary tangles in AD and fibrillar α-synuclein aggregation in the form of Lewy bodies and Lewy neurites in PD. Transmembrane protein 106B (TMEM106B) is a type II transmembrane lysosomal protein that participates in lysosome morphology, localization, acidification, and trafficking; t is involved in the pathogenesis of several NDs, especially frontotemporal lobular degeneration with TAR DNA-binding protein immunoreactive inclusions (FTLD-TDP). Studies from four independent research groups revealed that the luminal domain of TMEM106B (120-254aa) forms amyloid fibrils in several brain regions in patients with a series of NDs and neurologically normal older adults. Given its potentially critical roles in the pathogenesis of NDs and brain aging, this surprising finding has focused attention on TMEM106B and suggested that it is nearly as fundamental as other pathogenic amyloid proteins (e.g., Aβ, tau, α-syn); nevertheless, new questions surrounding TMEM106B must be asked. In this review,we firstly introduce the physiological function of TMEM106B and its involvement in NDs. Then, we elucidate the identification and cryo-electronic microscopic structure of TMEM106B fibrils and analyze the factors that contribute to the polymorphism of TMEM106B fibrils. Finally, the potential pathogenic role of TMEM106B fibrils is discussed, and the future directions for TMEM106 research in NDs are briefly summarized.

Uncovering single‐nucleus RNA velocity variations in neuropathologic Alzheimer’s disease

AbstractBackgroundDifferential single‐nucleus (snRNA‐seq) gene expression analyses in Alzheimer’s disease (AD) provide fixed snapshots of cellular alterations, failing to detect the temporal dynamics of genes at individual cells. To overcome this limitation, here we analyze single‐nucleus RNA velocities (RNA‐vel) from the prefrontal cortex to characterize dynamic genetic and cellular differences in neuropathological AD progression. RNA‐vel is the rate of change of gene expression obtained by comparing intronic and exonic sequence counts. Comparison of AD pathology associated gene expression with parallel RNA‐vel differences reveals sets of genes and molecular pathways that underlie the static and putative dynamic regimes of cell type‐specific dysregulations underlying the disease.MethodWe used snRNA‐seq data from the prefrontal cortex of 48 subjects1 with varied levels of AD pathology from ROSMAP2. We then calculated both the expression and RNA‐vel differences between low AD‐pathology and mild‐to‐severe AD‐pathology. These differences were cell‐specific across six major cell types: excitatory neurons, inhibitory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells.1. We characterized RNA‐vel differences associated with four AD neuropathology traits: neuritic plaque, neuronal neurofibrillary tangle, overall β‐amyloid load, and PHF tau tangle density.2. We demonstrated the reproducibility of the RNA‐vel differences in two independent datasets: dorsolateral prefrontal cortex (N = 24) from ROSMAP3 and superior frontal gyrus (N = 6) from GEO4.ResultOnly 10 of 843 (1.2%) genes overlap between the differential RNA expression and velocity analyses, suggesting substantial AD‐pathology related differences between these two RNA descriptors. The genes with only velocity differences relate to cell developmental and synaptic processes. Conversely, the genes with only differential expression are majorly associated with mitochondrial activity and ribosomal processes. Many genes were reproduced in the independent datasets; these overlapping genes are again associated with neural development and synaptic activities across many cell types, as well as vascular‐ and immune‐related processes in astrocytes and microglia, respectivelyConclusionWe use RNA velocity to characterize, for the first time to our knowledge, the dynamical multicellular processes underlying neuropathological AD progression. The results support the validity of the novel RNA‐vel concept for achieving a complementary molecular characterization of AD, which may be obscured by typical analysis of RNA abundance alone.

Pelargonidin and Berry Intake Association with Alzheimer's Disease Neuropathology: A Community-Based Study.

An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer's dementia risk. This study investigated if pelargonidin or berry intake is associated with Alzheimer's disease (AD) neuropathology in human brains. The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed. In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = -0.293 (0.14), p = 0.038), and fewer phosphorylated tau tangles (β (SE) = -0.310, p = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = -0.227 (0.11), p = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = -0.401 (0.16), p = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles. Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

Association of vitamin K with cognitive decline and neuropathology in community-dwelling older persons.

Higher vitamin K intakes have been associated with better cognitive function, suggestive of a vitamin K mechanistic effect or simply reflective of a healthy diet. To test the hypothesis that brain vitamin K is linked to cognitive decline and dementia, vitamin K concentrations were measured in four brain regions, and their associations with cognitive and neuropathological outcomes were estimated in 325 decedents of the Rush Memory and Aging Project. Menaquinone‐4 (MK4) was the main vitamin K form in the brain regions evaluated. Higher brain MK4 concentrations were associated with a 17% to 20% lower odds of dementia or mild cognitive impairment (MCI) (P‐value < .014), with a 14% to 16% lower odds of Braak stage ≥IV (P‐value < 0.045), with lower Alzheimer's disease global pathology scores and fewer neuronal neurofibrillary tangles (P‐value < 0.012). These findings provide new and compelling evidence implicating vitamin K in neuropathology underlying cognitive decline and dementia.

Healthy lifestyle, brain pathology, and cognition in community‐dwelling older adults

AbstractBackgroundLifestyle interventions for primary prevention of Alzheimer’s dementia recruit people at advanced ages who are at high risk of cognitive decline in the timeline of the trial. Given that Alzheimer’s disease and other dementia‐causing pathologies may accumulate in the brain years or even decades before older adults begin to show cognitive deficits, it is important to determine the association of lifestyle factors, cognition, and the role of dementia‐related brain pathologies.MethodUtilizing data from the Rush Memory and Aging Project, a longitudinal clinical‐pathologic study, we studied 566 decedents with lifestyle, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A healthy lifestyle score included being a non‐smoker, ≥150 min/week moderate/vigorous‐intensity physical activity, light‐to‐moderate alcohol consumption, MIND diet score &gt;7.5, and late‐life cognitive activity score &gt;3.2. Brain pathology included measures of beta‐amyloid, neuronal neurofibrillary tangles, Lewy body disease, hippocampal sclerosis, TDP‐43, cerebral infarcts, cerebral amyloid angiopathy, and arteriolosclerosis and atherosclerotic disease. The global cognitive score was derived from a comprehensive battery of nineteen standardized tests.ResultA higher healthy lifestyle score was associated with better global cognitive functioning proximate to death (beta=0.149, SE=0.036, p&lt;0.001) and slower annual cognitive decline (beta=0.014 units/year, SE=0.004, p&lt;0.001). A higher healthy lifestyle score was associated with less beta‐amyloid accumulation (beta=‐0.087, SE=0.041, p=0.034), but not with tangles, other neurodegenerative pathology, or indices of vascular pathology. Pathway analysis using structural equation modeling examined whether beta‐amyloid mediated the relationships between healthy lifestyle score and global cognition. Lifestyle score had a significant positive direct effect (beta=0.130, SE=0.035, p&lt;0.001) on global cognition. The indirect effect of lifestyle score on cognition through the pathway of beta‐amyloid load was also significant but had a relatively small effect size (beta=0.019, SE=0.009, p=0.045)ConclusionA healthy lifestyle was associated with better cognitive functioning even after accounting for dementia‐related brain pathologies, suggesting that lifestyle intervention may have cognitive benefits. Moreover, given that beta‐amyloid accumulates years to decades prior to the onset of cognitive decline, the indirect effect of lifestyle on cognition through beta‐amyloid may indicate that a healthy lifestyle could additionally provide primary prevention of Alzheimer’s disease and dementia.

Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer\u2019s disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aβ) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.

Fluorescent peptide nanoparticles to detect amyloid-beta aggregation in cerebrospinal fluid and serum for Alzheimer’s disease diagnosis and progression monitoring

Alzheimer’s disease (AD) is associated with the accumulation of insoluble forms of amyloid-beta (Aβ) in plaques in extracellular spaces, as well as in the walls of blood vessels, and aggregation of microtubule protein tau in neurofibrillary tangles in neurons. In this study, we designed and synthesized a series of fluorescent cyclic peptide nanoparticles (c-PNPs) that can be used to detect Aβ aggregates in both the cerebrospinal fluid (CSF) and serum, which were obtained from healthy people and AD patients in different disease stages. Our experimental studies indicate that the fluorescence intensities and wavelengths generated from the interactions between the negatively charged c-PNPs and Aβ aggregates in both the CSF and serum changed with disease status, as compared to healthy individuals. The morphological and cytotoxicity studies demonstrated a potential inhibitory effect of the negatively charged c-PNPs on amyloid fibril growth. The underlying mechanisms leading to these changes are interpreted based on the aromatic, hydrophobic, and electrostatic interactions between c-PNPs and Aβ peptides. These results indicate that the c-PNPs may provide a noninvasive and sensitive method for diagnosing AD and monitoring its progression.

Capacity for Seeding and Spreading of Argyrophilic Grain Disease in a Wild-Type Murine Model; Comparisons With Primary Age-Related Tauopathy.

Argyrophilic grain disease (AGD) is a common 4R-tauopathy, causing or contributing to cognitive impairment in the elderly. AGD is characterized neuropathologically by pre-tangles in neurons, dendritic swellings called grains, threads, thorn-shaped astrocytes, and coiled bodies in oligodendrocytes in the limbic system. AGD has a characteristic pattern progressively involving the entorhinal cortex, amygdala, hippocampus, dentate gyrus, presubiculum, subiculum, hypothalamic nuclei, temporal cortex, and neocortex and brainstem, thus suggesting that argyrophilic grain pathology is a natural model of tau propagation. One series of WT mice was unilaterally inoculated in the hippocampus with sarkosyl-insoluble and sarkosyl-soluble fractions from “pure” AGD at the age of 3 or 7/12 months and killed 3 or 7 months later. Abnormal hyper-phosphorylated tau deposits were found in ipsilateral hippocampal neurons, grains (dots) in the hippocampus, and threads, dots and coiled bodies in the fimbria, as well as the ipsilateral and contralateral corpus callosum. The extension of lesions was wider in animals surviving 7 months compared with those surviving 3 months. Astrocytic inclusions were not observed at any time. Tau deposits were mainly composed of 4Rtau, but also 3Rtau. For comparative purposes, another series of WT mice was inoculated with sarkosyl-insoluble fractions from primary age-related tauopathy (PART), a pure neuronal neurofibrillary tangle 3Rtau + 4Rtau tauopathy involving the deep temporal cortex and limbic system. Abnormal hyper-phosphorylated tau deposits were found in neurons in the ipsilateral hippocampus, coiled bodies and threads in the fimbria, and the ipsilateral and contralateral corpus callosum, which extended with time along the anterior-posterior axis and distant regions such as hypothalamic nuclei and nuclei of the septum when comparing mice surviving 7 months with mice surviving 3 months. Astrocytic inclusions were not observed. Tau deposits were mainly composed of 4Rtau and 3Rtau. These results show the capacity for seeding and spreading of AGD tau and PART tau in the brain of WT mouse, and suggest that characteristics of host tau, in addition to those of inoculated tau, are key to identifying commonalities and differences between human tauopathies and corresponding murine models.

Reader response: Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology.

We read with interest the article by Arvanitakis et al.,1 which found that both higher mean and more rapidly declining late-life systolic blood pressure (SBP) increased the odds of gross and microinfarcts. A relationship between higher mean SBP and neuronal neurofibrillary tangles was also observed. In examining blood pressure (BP) and neuropathology of aging, recent work highlighted that high—but also low BP—and wide fluctuations of BP levels may increase the risk of dementia, including mixed or Alzheimer dementia.2–4 In addition, antihypertensive medications can specifically address the pulsatile component and variability of BP.4,5 Therefore, it would be interesting to explore whether and how BP variability and pulse pressure relate to brain disease. These analyses would be useful to further understand the vascular contribution to cognitive dysfunction and identify potential therapeutic strategies.

Polygenic hazard score, amyloid deposition and Alzheimer's neurodegeneration.

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-β protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.

Nodding syndrome in Uganda is a tauopathy

Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13–18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving the cerebral cortex, subcortical nuclei and brainstem. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving the crests of gyri and the superficial cortical lamina. The mesencephalopontine tegmental nuclei, substantia nigra, and locus coeruleus revealed globose neurofibrillary tangles and threads. We conclude that nodding syndrome is a tauopathy and may represent a newly recognized neurodegenerative disease.

Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

Puerarin inhibits β-amyloid peptide 1-42-induced tau hyperphosphorylation via the Wnt/β-catenin signaling pathway

Excessive tau protein phosphorylation is important in the pathogenesis and early abnormal signal transduction of Alzheimer's disease. Excessive phosphorylation of microtubules is associated with tau accumulation, which induces the formation of neurofibrillary tangles in neurons, leading to synaptic damage and ultimately, neurodegeneration. The present study aimed to investigate the possible mechanism underlying the inhibitory effects of puerarin on β‑amyloid peptide (Aβ)1‑42‑induced tau protein hyperphosphorylation in SH‑SY5Y cells. Following various treatments, the viability of SH‑SY5Y cells was determined using the MTT assay, and cell morphology was observed under an inverted fluorescence microscope. Western blotting was used to detect tau phosphorylation, and the protein expression levels of glycogen synthase kinase (GSK)‑3β, phosphorylated (p)‑GSK‑3β (Ser9), β‑catenin and cyclin D1, which are the key factors mediating the Wnt/β‑catenin signaling pathway in SH‑SY5Y cells. The results demonstrated that puerarin reversed the Aβ1‑42‑induced decrease in SH‑SY5Y cell viability. In addition, puerarin inhibited the degree of Aβ1‑42‑induced tau phosphorylation at Ser396, Ser199 and Thr231 in SH‑SY5Y cells, and reduced the expression of GSK‑3β by increasing the expression of p‑GSK‑3β (Ser9). Furthermore, puerarin increased the protein expression levels of β‑catenin and cyclin D1, which are key factors involved in the Wnt/β‑catenin signaling pathway. The results of the present study demonstrated that puerarin may attenuate Aβ1‑42‑induced tau hyperphosphorylation in SH‑SY5Y cells, by inhibiting the expression of GSK‑3β and activating the Wnt/β‑catenin signaling pathway; therefore, puerarin may exert protective effects against Alzheimer's disease.

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease.

BackgroundThe blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer’s disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients.MethodsWe determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed the specific and direct effects of such molecules on BBB integrity in vitro using human primary brain microvascular endothelial cells or a cell line.ResultsWe observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects). Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients. In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients. Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands. Pre-treatment with anti-HMGB1 monoclonal antibody blocked HMGB1 effects and leaving BBB integrity intact.ConclusionsOur current studies indicate that thrombin and HMGB1 are causal proximate proinflammatory mediators of BBB dysfunction, while sTM levels may indicate BBB endothelial damage; HMGB1 and sRAGE might serve as clinical biomarkers for progression and/or therapeutic efficacy along the AD spectrum.

Temporal course of neurodegenerative effects on cognition in old age.

To test the hypothesis that different forms of neurodegeneration are differentially related to longitudinal cognitive trajectories in old age. Participants are 420 older persons from 2 clinical-pathologic studies without cognitive impairment at study onset. They completed a battery of 17 cognitive tests annually for a minimum of 5 years, died, and underwent a neuropathologic examination to quantify neuronal neurofibrillary tangles and transactive response DNA-binding protein 43 (TDP-43) pathology and to identify Lewy bodies and hippocampal sclerosis. The authors used sigmoid mixed models based on the 4-parameter logistic distribution to decompose nonlinear global cognitive trajectories into components and assess the relation of each neuropathologic marker to each trajectory component. Cognitive function was assessed for a mean of 10.5 years before death. In the absence of pathology, global cognition was relatively stable before declining moderately in the last 3 to 4 years of life. Tangles were related to all trajectory components except initial level. TDP-43 pathology was the only marker related to initial level of function. It was also associated with an earlier midpoint of decline but not to slope of decline. Hippocampal sclerosis was related to an earlier midpoint of decline and more rapid slope of decline. Lewy bodies were associated with faster slope of decline and lower level of function proximate to death. Neurodegenerative processes are differentially related to cognitive trajectories, with TDP-43 pathology most potently impacting incipient cognitive decline, AD pathology and hippocampal sclerosis affecting the progression of cognitive decline, and Lewy bodies impacting terminal decline. (PsycINFO Database Record