Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer’s disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair. Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy

Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates.

Genetic mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). Although mitochondrial dysfunction and stress granule have been crucially implicated in FUS proteinopathy, the molecular basis remains unclear. Here, we show that DHX30, a component of mitochondrial RNA granules required for mitochondrial ribosome assembly, interacts with FUS, and plays a crucial role in ALS-FUS. WT FUS did not affect mitochondrial localization of DHX30, but the mutant FUS lowered the signal of mitochondrial DHX30 and promoted the colocalization of cytosolic FUS aggregates and stress granule markers. The immunohistochemistry of the spinal cord from an ALS-FUS patient also confirmed the colocalization, and the immunoelectron microscope demonstrated decreased mitochondrial DHX30 signal in the spinal motor neurons. Subcellular fractionation by the detergent-solubility and density-gradient ultracentrifugation revealed that mutant FUS also promoted cytosolic mislocalization of DHX30 and aggregate formation. Interestingly, the mutant FUS disrupted the DHX30 conformation with aberrant disulfide formation, leading to impaired mitochondrial translation. Moreover, blue-native gel electrophoresis revealed an OXPHOS assembly defect caused by the FUS mutant, which was similar to that caused by DHX30 knockdown. Collectively, our study proposes DHX30 as a pivotal molecule in which disulfide-mediated conformational change mediates mitochondrial dysfunction and cytosolic aggregate formation in ALS-FUS

Tau beyond Tangles: DNA Damage Response and Cytoskeletal Protein Crosstalk on Neurodegeneration

Neurons in the brain are continuously exposed to various sources of DNA damage. Although the mechanisms of DNA damage repair in mitotic cells have been extensively characterized, the repair pathways in post-mitotic neurons are still largely elusive. Moreover, inaccurate repair can result in deleterious mutations, including deletions, insertions, and chromosomal translocations, ultimately compromising genomic stability. Since neurons are terminally differentiated cells, they cannot employ homologous recombination (HR) for double-strand break (DSB) repair, suggesting the existence of neuron-specific repair mechanisms. Our research has centered on the microtubule-associated protein tau (MAPT), a crucial pathological protein implicated in neurodegenerative diseases, and its interplay with neurons’ DNA damage response (DDR). This review aims to provide an updated synthesis of the current understanding of the complex interplay between DDR and cytoskeletal proteins in neurons, with a particular focus on the role of tau in neurodegenerative disorders

Idiopathic Normal Pressure Hydrocephalus has a Different Cerebrospinal Fluid Biomarker Profile from Alzheimer's Disease.

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimer's disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD

Two-Point Dynamic Observation of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus

Background: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. Objective: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. Methods: We analyzed CSF concentrations of tau, amyloid-β (Aβ) 42 and 40, and leucine rich α-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). Results: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aβ₄₂ (LD/FD = 0.80, p <  0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p <  0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with concentrations of tau (p = 0.02) and LRG (p = 0.04), respectively. Conclusions: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness

Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice.

Accumulating evidence suggests that some dietary patterns, specifically high fat diet (HFD), increase the risk of developing sporadic Alzheimer disease (AD). Thus, interventions targeting HFD-induced metabolic dysfunctions may be effective in preventing the development of AD. We previously demonstrated that amyloid precursor protein (APP)-overexpressing transgenic mice fed HFD showed worsening of cognitive function when compared with control APP mice on normal diet. Moreover, we reported that voluntary exercise ameliorates HFD-induced memory impairment and β-amyloid (Aβ) deposition. In the present study, we conducted diet control to ameliorate the metabolic abnormality caused by HFD on APP transgenic mice and compared the effect of diet control on cognitive function with that of voluntary exercise as well as that of combined (diet control plus exercise) treatment. Surprisingly, we found that exercise was more effective than diet control, although both exercise and diet control ameliorated HFD-induced memory deficit and Aβ deposition. The production of Aβ was not different between the exercise- and the diet control-treated mice. On the other hand, exercise specifically strengthened the activity of neprilysin, the Aβ-degrading enzyme, the level of which was significantly correlated with that of deposited Aβ in our mice. Notably, the effect of the combination treatment (exercise and diet control) on memory and amyloid pathology was not significantly different from that of exercise alone. These studies provide solid evidence that exercise is a useful intervention to rescue HFD-induced aggravation of cognitive decline in transgenic model mice of AD

High fat diet enhances β-site cleavage of amyloid precursor protein (APP) via promoting β-site APP cleaving enzyme 1/adaptor protein 2/clathrin complex formation

Obesity and type 2 diabetes are risk factors of Alzheimer's disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by β-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP- 2/clathrin complex, increasing the level of the soluble form of APP β (sAPPβ). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPβ. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of β-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage

Nokkur orð um lichen planus

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn Skoða/Opna(view/open)Þegar ritstjóri Tannlæknablaðsins bað mig um að skrifa nokkur orð um lichen planus (flatskæning) ákvað ég að sleppa því að minnast á flest það sem talað er um í al-gengum kennslubókum og takmarka umræðuna við mínar eigin athuganir á þessum algenga sjúkdómi. Engar faraldsfræðilegar rannsóknir hafa verið fram-kvæmdar á lichen planus á íslandi en gera má ráð fyrir því að tíðni flatskænings á húð og/eða munnslímhúð þjóðar-innar sé um 2%. Þó að lichen planus sé algengt á munns-límhúð er tíðnin á húð enn hærri. Oftast sést lichen planus á sjúklingum um og yfir fertugt en jafnvel hefur orðið vart við nokkur tilfelli hjá skólabörnum

HFD after exercising increased Aβ oligomer as well as deposited Aβ levels in APP-HFD mice.

<p>(<i>A</i>) Immunohistochemical analysis using anti-Aβ (6E10) antibody. Representative images of Aβ-immunostained hippocampus sections from control APP, APP-HFD, APP-HFD+Ex 0–10, APP-HFD+Ex 5–15 and APP-HFD+Ex 10–20 mice, respectively. Scale bar, 0.5 mm. Increase of Aβ deposition was observed in APP-HFD+Ex 0–10and APP-HFD+Ex 5–15 mice compared with that in APP-HFD+Ex 10–20 mice. However, the amount of Aβ deposition in APP-HFD+Ex 0–10 mice and APP-HFD+Ex 5–15 mice was less than that in APP-HFD mice. (<i>B</i>) The amount of Aβ 40 in FA fraction of control APP, APP-HFD, APP-HFD+Ex 0–10, APP-HFD+Ex 5–15 and APP-HFD+Ex 10–20 mice was analyzed by ELISA. Aβ 40 level in FA fraction of APP-HFD+Ex 0–10 mice was higher than that of APP-HFD+Ex 10–20 mice (F _{(4, 15)}  = 10.40, p = 0.009). However, the amount of Aβ 40 in APP-HFD+Ex 0–10 mice (p = 0.028) and APP-HFD+Ex 5–15 mice (p = 0.004) was less than that in APP-HFD mice. * indicated p<0.05. (<i>C</i>) The amount of Aβ 42 in FA fraction of control APP, APP-HFD, APP-HFD+Ex 0–10, APP-HFD+Ex 5–15 and APP-HFD+Ex 10–20 mice was analyzed by ELISA. There was no statistically significant difference in the level of Aβ 42 among APP-HFD+Ex 0–10, APP-HFD+Ex 5–15 and APP-HFD+Ex 10–20 mice (F _{(4, 15)}  = 24.4). However, the amount of Aβ 42 in APP-HFD+Ex 0–10 mice (p<0.001) and APP-HFD+Ex 5–15 mice (p<0.001) was lower than that in APP-HFD mice. * indicated p<0.05. (<i>D</i>) The amount of Aβ oligomer in the TBS-soluble fraction of control APP, APP-HFD, APP-HFD+Ex 0–10, APP-HFD+Ex 5–15 and APP-HFD+Ex 10–20 mice was analyzed by ELISA. The level of Aβ oligomer in TBS fraction of APP-HFD+Ex 0–10 mice was higher than that of APP-HFD+Ex 10–20 mice (F _{(4, 15)}  = 3.33, p = 0.035). The amount of Aβ oligomer in APP-HFD+Ex 0–10 mice was the same as that in APP-HFD mice. * indicated p<0.05. (<i>E</i>) The amount of Aβ oligomer in the TBS-soluble fraction of control APP, APP-HFD, APP-HFD+Ex 0–10, APP-HFD+Ex 5–15 and APP-HFD+Ex 10–20 mice was analyzed by filter trap assay using anti-oligomer (A11) antibody to detect oligomeric Aβ. Representative images of dot are shown in upper panel. Statistical analysis of dot density is described at the bottom. The average dot density of the control APP samples was regarded as 100% and that of other groups was relatively indicated. The relative density of APP-HFD+Ex 0–10 mice was higher than that of APP-HFD+Ex 10–20 mice (F _{(4, 10)}  = 12.69, p = 0.007). The dot density of Aβ oligomer in APP-HFD+Ex 0–10 mice was the same as that in APP-HFD mice. * indicated p<0.05.</p