Effect of exogenous trivalent iron ions on tau phosphorylation and aggregation in SH-SY5Y cells / 环境与职业医学

Background A large amount of iron deposition in the brain can cause neuronal damage by inducing oxidative stress, neuroinflammation, and abnormal mitochondrial function. In addition, iron deposition is also reported to be closely related to the pathogenesis of Alzheimer's disease (AD). The neurofibrillary tangles aggregated by tau hyperphosphorylation are one of the important pathological features of AD. Objective To investigate potential effect of exogenous trivalent iron ions on neuronal activity in human neuroblastoma (SH-SY5Y) cells and tau hyperphosphorylation and aggregation. Methods SH-SY5Y cells were treated with ferric chloride (FeCl3) at four concentrations (10, 100, 200, and 400 mg·L−1). Cell survival rate was then detected by CCK8 assay. Intracellular iron content was determined prussian blue (Perl's) by iron staining after 24 h exposure to FeCl3 at 10 or 200 mg·L−1. Transfection of tau-P301L plasmid was conducted to construct an AD-like cell model for tau overexpression. The differences in the expression of the phosphorylated tau (p-tau) protein in SH-SY5Y cells and SH-SY5Y cells with tau overexpression were detected by Western blotting after 24 h exposure to FeCl3 at 10 and 200 mg·L−1. After dilution with phosphate buffered saline (PBS), FeCl3, human tauR3, and FeCl3 + tauR3 were incubated at 37℃, and the fluorescence intensity reflecting tau aggregation level was measured by thioflavin T(ThT) method at 12, 24, 36, 48, 60, 72, 84, and 96 h, respectively. Meanwhile, after 96 h coincubation of FeCl3 and tauR3, the fibers formed by tau aggregation were observed under a transmission electron microscope (TEM). Results After 24 h of FeCl3 exposure, the cell survival rate of SH-SY5Y cells among all groups was statistically different (F=8.63, P<0.01). The cell survival rates in the 200 and 400 mg·L−1 groups were 80.1% and 68.7% of the control group, respectively (P<0.05). Compared with the control group, the nuclei of the 200 mg·L−1 FeCl3 group were mainly yellowish-brown after iron staining and the positive cell rate was up-regulated by 12.9% (P<0.01). After 24 h of FeCl3 exposure , the p-tau (Ser396) protein expression was statistically different among all groups (F=11.6, P<0.01). Compared with the control group, the p-tau protein expression level of SH-SY5Y cells in the 200 mg·L−1 group was up-regulated by 72.7% (P<0.01). After FeCl3-treated SH-SY5Y cells with tau overexpression for 24 h, the p-tau (Ser396) protein expression was statistically different among all groups (F=27.8, P<0.01). Compared with the tau group, the p-tau (Ser396) protein expression level of SH-SY5Y cells in the tau + 200 mg·L−1 group was up-regulated by 44.6% (P<0.05). Compared with the tauR3 group, the fluorescence intensities in the 84 and 96 h tauR3 + FeCl3 groups were up-regulated by 49.9% and 53.7% (P<0.01) respectively. After 96 h of coincubation, compared with the tauR3 group, FeCl3 + tauR3 aggravated tau aggregation and formed fiber deposition under TEM. Conclusion Exogenous trivalent iron ions may inhibit SH-SY5Y cell viability, promote the phosphorylation of tau in SH-SY5Y cells transfected with tau-P301L plasmid, and aggravate tauR3 aggregation and fiber production.

Primary age-related tauopathy in a Chinese cohort / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Primary age-related tauopathy (PART) is characterized by the presence of tau neurofibrillary tangles (NFTs) which are typically observed in Alzheimer's disease (AD) brains, with few or without β-amyloid (Aβ) plaques. The diagnosis of PART can be categorized into "definite" or "possible" depending on the amount of Aβ plaques. Definite PART is diagnosed when NFTs are observed and the Braak stage is ≤IV, with Thal Aβ Phase 0 (Crary et al., 2014). According to the neuropathological diagnostic criteria, we reported that PART was frequently observed in the Chinese population according to our findings from specimens in our brain bank, with 47% of brain bank subjects meeting the criteria for PART. There is no consensus on the nature of PART. It remains to be elucidated whether PART is an early form of AD or a novel tauopathy (Duyckaerts et al., 2015; Jellinger et al., 2015).

Neurofibriilary tangle-predominant dementia / 中华老年医学杂志

Neurofibrillary tangle-predominant dementia (NFTPD)is one type of late-onset dementia,with memory disorders as the main clinical manifestation.The pathological feature is the presence of a large number of neurofibrillary tangle(NFT)in the hippocampus with no or little amyloid deposition in the brain.In recent years,primary age-related tauopathy(PART)has been proposed as a new pathological term,which means that NFT appears in the medial temporal lobe with aging,but no amyloid deposits,and NFTPD is one type of dementia associated with the progression of PART.

Neurofibrillary tangle-predominant dementia / 中华老年医学杂志

Neurofibrillary tangle-predominant dementia(NFTPD)is one type of late-onset dementia, with memory disorders as the main clinical manifestation.The pathological feature is the presence of a large number of neurofibrillary tangle(NFT)in the hippocampus with no or little amyloid deposition in the brain.In recent years, primary age-related tauopathy(PART)has been proposed as a new pathological term, which means that NFT appears in the medial temporal lobe with aging, but no amyloid deposits, and NFTPD is one type of dementia associated with the progression of PART.

Phosphorylated TDP-43 Staging of Primary Age-Related Tauopathy / 神经科学通报·英文版

Primary age-related tauopathy (PART) is characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. In the present study, we analyzed the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART, Alzheimer's disease (AD), and aging control cases. We examined the regional distribution patterns of pTDP-43 intraneuronal inclusions in PART with Braak NFT stages > 0 and ≤ IV, and a Thal phase of 0 (no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of pTDP-43 in PART. Stage I was characterized by the presence of pTDP-43 lesions in the amygdala, stage II by such lesions in the hippocampus, stage III by spread of pTDP-43 to the neocortex, and stage IV by pTDP-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of pTDP-43 pathology in PART cases was similar to the early TDP-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of pTDP-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the pTDP-43 stage and density.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease / 神经科学通报·英文版

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

Scutellaria barbata flavonoids inhibits NFT aggregation and regulatory mechanism in rats induced by composited Aβ / 中国病理生理杂志

AIM: To investigate the effects of Scutellaria barbata flavonoids (SBF) on neurofibrillary tangle (NFT) aggregation, tau protein phosphorylation and the regulated mechanism of glycogen synthase kinase (GSK) 3βand protein phosphatase (PP) 2A in the rats induced by amyloid βprotein 25-35 (Aβ25-35) in combination with AlCl3 and re-combinant human transforming growth factor ( RHTGF)-β1( composited Aβ) .METHODS:The male SD rats were used to establish the simulated Alzheimer disease ( AD) model by intracerebroventricular injection of composited Aβ.The Morris water maze was applied for screening the successful model rats with learning and memory deficits .The successful model rats were daily and orally administrated with SBF at doses of 35, 70 and 140 mg/kg or positive control drug Ginkgo biloba leaves flavonoids ( GLF) at 140 mg/kg for 37 d.The silver nitrate staining was used to determine the cortical NFT .The protein levels of total tau, phosphorylated protein of tau at Ser199 and Ser214 sites, GSK3βand PP2A in hippocampus and cortex were determined by Western blot .The mRNA expression of GSK3βand PP2A in the hippocampus and cortex was detected by RT-PCR.RESULTS:Compared with sham group , the cell number of positive NFT with silver nitrate staining in model rat cerebral cortex was significantly increased .The protein levels of phosphorylated tau protein at Ser 199 and Ser214 sites, GSK3βin the hippocampus and cerebral cortex in the model rats dramatically elevated , and PP2A was marked decreased as compared with the sham group rats.Meanwhile, the mRNA expression of GSK-3βsignificantly increased but PP2A was de-creased.However, these above abnormalities were differently attenuated by treating with SBF at different doses or GLF at 140 mg/kg for 37 d.CONCLUSION: SBF suppresses the NFT aggregation by inhibition of the regulatory functions of GSK-3βand PP2A, thus reducing the phosphorylation of tau protein .

Alzheimer's Disease: Report of two cases

Alzheimer's disease (AD) is the most common etiology of dementia, that has not been previously reported in Korea. We have experienced two cases of Alzheimer's disease, one occurred in a 53-year-old man with dementia and the other occurred in a 36-year-old woman with a family history of early onset dementia. A neocortical biopsy was done to rule out the cause of dementia and showed diffusely scattered numerous senile plaques and neurofibrillary tangles in cortex of both cases. Interestingly, GFAP, an immunohistochemical stain showed strong positivity in neuritic plaques and the surrounding fibrillary gathering.

Alzheimer's Disease: Report of two cases

Alzheimer's disease (AD) is the most common etiology of dementia, that has not been previously reported in Korea. We have experienced two cases of Alzheimer's disease, one occurred in a 53-year-old man with dementia and the other occurred in a 36-year-old woman with a family history of early onset dementia. A neocortical biopsy was done to rule out the cause of dementia and showed diffusely scattered numerous senile plaques and neurofibrillary tangles in cortex of both cases. Interestingly, GFAP, an immunohistochemical stain showed strong positivity in neuritic plaques and the surrounding fibrillary gathering.

Tau protein and Alzheimers disease / 中国药理学通报

Tau is a multifunctional protein that are originally identified as a microtubule-associated protein. Tau is mainly expressed in neurons. There is a protein phosphorylation/dephosphorylation imbalance and tau is abnormally hyperphosphorylatied in the brain of patients with AD and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles(PHF/NFT). The modulation of the activities of phosphatase(PP)-2A, PP1 and tau kinase, such as GSK-3, cdk5 and MAPK effect tau protein hyperphosphorylation. It is unclear about the relation between tau and A? in AD, increased or altered A? production may be an initiating event in the pathogenic process in AD; but aberrant alternations in tau function are likely necessary for the subsequent neuronal dysfunction and death. Therefore, clearly defining the metabolism and function of tau in both normal and disease states is necessary for our understanding of AD and the development of appropriate therapeutic interventions.