Ginsenoside Rh4 Alleviates Amyloid ß Plaque and Tau Hyperphosphorylation by Regulating Neuroinflammation and the Glycogen Synthase Kinase 3ß Signaling Pathway.

Alzheimer's disease (AD) is a primary neurodegenerative disease. It can be caused by aging and brain trauma and severely affects the abilities of cognition and memory of patients. Therefore, it seriously threatens the mental and physical health of humans worldwide. As a traditional Chinese medicine, ginsenosides have been proven to have a variety of pharmacological activities. Ginsenoside Rh4 (Rh4) is one of the rare ginsenosides with higher pharmacological activity than ordinary ginsenosides, but its effect on alleviating AD and its molecular mechanism have not been studied. Here, we investigated the anti-AD effects of Rh4 and its potential mechanisms using an AD mouse model induced by a combination of AlCl3·6H2O and d-galactose. The results showed that Rh4 could significantly improve the ability of cognizance and reduce neuronal damage in mice. Concurrently, Rh4 attenuates amyloid ß accumulation, increases the density of dendritic spines, and logically inhibits synaptic structural damage as a result of neuronal excessive apoptosis and autophagy. Rh4 can not only inhibit the inflammatory response caused by the overactivation of microglia and astrocytes, reduce the levels of pro-inflammatory factors, increase the level of antioxidant enzymes in serum, and significantly improve the activity of antioxidant enzyme SOD1 in the hippocampus but also inhibit the hyperphosphorylation of tau protein in the hippocampus of mice by regulating the Wnt2b/GSK-3ß/SMAD4 signaling pathway. Together, this study provides a theoretical basis for Rh4 in the treatment of AD and reveals that Rh4 is a potential drug for the treatment of AD.

Genetically Engineered Triple MAPT-Mutant Human-Induced Pluripotent Stem Cells (N279K, P301L, and E10+16 Mutations) Exhibit Impairments in Mitochondrial Bioenergetics and Dynamics.

Pathological abnormalities in the tau protein give rise to a variety of neurodegenerative diseases, conjointly termed tauopathies. Several tau mutations have been identified in the tau-encoding gene MAPT, affecting either the physical properties of tau or resulting in altered tau splicing. At early disease stages, mitochondrial dysfunction was highlighted with mutant tau compromising almost every aspect of mitochondrial function. Additionally, mitochondria have emerged as fundamental regulators of stem cell function. Here, we show that compared to the isogenic wild-type triple MAPT-mutant human-induced pluripotent stem cells, bearing the pathogenic N279K, P301L, and E10+16 mutations, exhibit deficits in mitochondrial bioenergetics and present altered parameters linked to the metabolic regulation of mitochondria. Moreover, we demonstrate that the triple tau mutations disturb the cellular redox homeostasis and modify the mitochondrial network morphology and distribution. This study provides the first characterization of disease-associated tau-mediated mitochondrial impairments in an advanced human cellular tau pathology model at early disease stages, ranging from mitochondrial bioenergetics to dynamics. Consequently, comprehending better the influence of dysfunctional mitochondria on the development and differentiation of stem cells and their contribution to disease progression may thus assist in the potential prevention and treatment of tau-related neurodegeneration.

[Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats].

OBJECTIVE: To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD. METHODS: A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3ß (GSK-3ß) in the hippocampus was detected. RESULTS: There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3ßwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3ß was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05). CONCLUSION: Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3ß and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats / 中国针灸

OBJECTIVE@#To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD.@*METHODS@#A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β) in the hippocampus was detected.@*RESULTS@#There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3βwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3β was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05).@*CONCLUSION@#Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3β and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

[Effects of pre-moxibustion on expression of phosphorylated Tau protein and related protein kinases in hippocampal CA3 region of AD rats].

OBJECTIVE: To observe the effect of pre-moxibustion at "Baihui"(GV20), "Shenshu"(BL23) and "Zusanli"(ST36) on expression of Tau protein and related protein kinases as glycogen synthase kinase-3ß (GSK-3ß), etc. in the hippocampal CA3 region of Alzheimer's disease (AD) rats, so as to explore its mechanism underlying prevention and treatment of AD cognitive impairment. METHODS: Male SD rats were randomly divided into 4 groups: normal control, sham operation， model and pre-moxibustion，with 9 rats in each group. Rats of the pre-moxibustion group received moxibustion of GV20, BL23 and ST36 for 15 min, once a day, 6 days a week for 3 weeks. After completion of moxibustion, the AD model was reproduced by injection of amyloid beta-peptide 25-35(Aß 25-35) aggregation solution 1 µL (5 µg/µL) into the bilateral hippocampus, rats of the sham operation group received injection of the same dose of normal saline into the hippocampus. The spatial learning-memory ability was detected using Morris water maze test, and changes of the ultrastructure of hippocampal neurons were observed using electron microscope, and those of histopathological changes of hippocampus tissue observed using hematoxylin eosin (H.E.) staining. The expression levels of hippocampal GSK-3ß, p-Tau, CDK5 and Synapsin I proteins were detected by Western blot and immunohistochemistry, respectively. RESULTS: No significances were found between the normal control and sham groups in all the indexes (P>0.05). Compared with the control group, the escape latency of place navigation test of Morris water maze test, expression of GSK-3ß and CDK5 and the immunoactivity of GSK-3ß, CDK5 and p-Tau were significantly increased (P<0.01), and the residence time in the platform quadrant and the number of platform crossing of spatial prob test and the expression of Synapsin Ⅰ significantly reduced in the model group (P<0.01). Following the intervention, the increase of escape latency, expression of GSK-3ß and CDK5 and the immunoactivity of GSK-3ß, CDK5 and p-Tau, and the decrease of residence time in the platform quadrant, number of platform crossing and the expression of Synapsin Ⅰ were reversed in the pre-moxibustion group (P<0.05, P<0.01). Outcomes of ultrastructure and histopathological observations respectively showed edema of hippocampal nerve cells at varying degrees, moderate edema of the cytoplasma, chromatin condensation at the edge of the nucleus, partial mitochondrial vacuole-like degeneration, fracture of tubular crest, edema and expansion of Golgi body, disappearance of polarity, fracture of the rough endoplasmic reticulum, degeneration of ribosome and partial myelin axon and reduced synaptic vesicles in the presynaptic capsule; and reduced number of neurons with shrank body, disappearance of nucleolus and blurred nuclear boundary and vacuole-like degeneration in some of them in the model group, which were relatively milder in the pre-moxibustion group. CONCLUSION: Pre-moxibustion at GV20, BL23 and ST36 plays a role in slowing down the occurrence and development of cognitive impairment in AD rats, which may be related to its functions in inhibiting tau protein hyperphosphorylation and reducing the expression of some related protein kinases in the hippocampus.

[Electroacupuncture improves learning-memory ability by down-regulating expression of hippocampal Aß1-42 and Tau and NF-κB proteins in diabetic rats with cognitive impairment].

OBJECTIVE: To observe the effect of electroacupuncture(EA) on the expression of nuclear transcription factors κB (NF-κB) and Tau protein and content of amyloid (Aß) in diabetic rats with cognitive impairment, so as to explore its mechanism underlying improvement of learning-memory ability. METHODS: Male SD rats were randomly divided into normal control (n=9), model (n=9) and EA (n=9) groups. The diabetic mellitus model was established by feeding the rats with high fat and high sugar for 1 month and intraperitoneal injection of STZ (25 mg·kg-1·d-1) for 2 days. EA was applied to "Zusanli"(ST36) and "Neiting"(ST44) for 20 min, alternatively on both side every day, and "Yishu"(EX-B3) was stimulated by twirling the acupuncture needle with uniform reinforcing-reducing method for 1 min, followed by retaining it for 20 min. The treatment was conducted 6 times a week for 4 weeks. The learning-memory ability was evaluated by using Morris water maze swimming test. The blood glucose level was randomly detected by using a glucometer, the content of Aß1-42 in the hippocampal tissue was detected by ELISA, and the relative expression levels of hippocampal Tau and NF-κB p65 proteins and mRNAs were determined by Western blot and fluorescence quantitative real-time PCR, separately. RESULTS: After modeling, the blood glucose, escape latency, Aß1-42 content and the expression levels of Tau and NF-κB p65 proteins and mRNAs in the model group were significantly increased (P<0.01, P<0.05) in comparison with the normal control group. Following EA intervention, the modeling induced increase of blood glucose, escape latency, Aß1-42 content and the expression levels of Tau and NF-κB p65 proteins and mRNAs were reversed (P<0.05, P<0.01). CONCLUSION: EA can improve the learning-memory ability in rats with diabetic cognitive impairment, which may be related to its function in down-regulating the levels of hippocampal Aß1-42, Tau and NF-κB proteins.

Acupuncture Effect Assessment in APP/PS1 Transgenic Mice: On Regulating Learning-Memory Abilities, Gut Microbiota, and Microbial Metabolites.

Alzheimer's disease (AD) is a brain illness that affects learning and memory capacities over time. In recent investigations, acupuncture has been shown to be an effective alternative treatment for AD. We investigated the effect of acupuncture on learning and memory abilities using a water maze in APP/PS1 transgenic mice. The amounts of Aß and tau protein in mice's hippocampal tissue were determined using Western blot. The levels of IL-1ß, IL-10, LPS and TNF-α in mice's serum were measured using ELISA. The variations of gut microbiota in mice's feces were determined using the 16SrDNA technique, and the metabolites were examined using a untargeted metabolomics methodology. The results showed that acupuncture treatment improved mice's learning and memory abilities substantially. Acupuncture therapy regulated the Aß and tau protein concentration as well as the levels of IL-10 and LPS. Acupuncture treatment influenced the mouse microbiota and metabolites and had been linked to six biochemical pathways. This study adds to our understanding of the effect of acupuncture on AD and opens the door to further research into the alterations of intestinal bacteria in the presence of AD.

An Adequate Supply of Bis(ethylmaltolato)oxidovanadium(IV) Remarkably Reversed the Pathological Hallmarks of Alzheimer's Disease in Triple-Transgenic Middle-Aged Mice.

Alzheimer's disease (AD) is a complex and progressive neurodegenerative disease with impaired synapse, imbalanced mineral metabolism, protein mis-folding and aggregation. Bis(ethylmaltolato)oxidovanadium(IV) (BEOV), an organic bioactive vanadium compound with low toxicity and high bioavailability, has been studied as therapeutic agent against tuberculosis and diabetes. However, its neuroprotective effects have rarely been reported. Therefore, in this study, the potential application of BEOV in intervening AD cognitive dysfunction and neuropathology was evaluated. Both low- and high-dose of BEOV (0.2 mmol/L and 1.0 mmol/L) supplementation for 2 months improved the spatial learning and memory deficits of the triple-transgenic AD (3 × Tg AD) mice and mitigated the loss of synaptic proteins and synaptic dysfunction. By inhibiting the expression of amyloid-ß precursor protein and ß-secretase, and the phosphorylation of tau protein at Ser262, Ser396, Ser404, and Ser202/Thr205 residues, BEOV reduced the amyloid-ß deposition and neurofibrillary tangle formation in AD mouse brains and primarily cultured neurons. Further analysis of the brain ionome revealed that BEOV supplementation could significantly affect the concentrations of a variety of metals, most of which, including several AD risk metals, showed reduced levels, particularly with a high-dose intake. Additionally, the elemental correlation network identified both conserved and specific elemental correlations, implying a highly complex and dynamic crosstalk between vanadium and other elements during long-term BEOV supplementation. Overall, our results suggest that BEOV is effective in AD intervention via both ameliorating the disease related pathology and regulating metal homeostasis.

The modulatory role of prime identified compounds in Geophila repens in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease via attenuation of cholinesterase, ß-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Geophila repens (L.) I.M. Johnst (Rubiaceae) is a small perennial creeper native to India, China, and other countries in Southeast Asia. The hot decoction of leaves is used orally for memory enhancing by the local folk of Andhra Pradesh, India. The ethnomedicinal claim of G. repens as memory enhancer was initially studied by the authors. Results demonstrated the important antioxidant and anticholinesterase activities of isolated molecule Pentylcurcumene and bioactive hydroalcohol extract of leaves of G. repens (GRHA). AIM OF THE STUDY: Based on the previous findings, additional research is needed to examine the efficacy of GRHA for memory enhancing properties. We therefore investigated the modulatory role of prime identified compounds in GRHA in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease (AD) via attenuation of cholinesterase, ß-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation. METHODS: Scopolamine (3 mg/kg) induced experimental rats of AD were treated with GRHA (300, 400 mg/kg) for 14 days. During the experimental period, elevated T-maze and locomotion-activity were performed to assess learning and memory efficacy of GRHA. At the end of the experiment, biochemical, neurochemical, neuroinflammation and histopathological observation of brain cortex were examined. GC-MS/MS analysis reported 31 compounds, among them 8 bioactive compounds possess antioxidant, neuroinflammation, neuroprotective activities, and were considered for docking analysis towards cholinesterase, ß-secretase activities in AD. RESULTS: GRHA 400 significantly improved learning and memory impairment with the improvement of oxidative stress (MDA, SOD, GSH, CAT), DNA damage (8-OHdG), neurochemical (AChE, BuChE, BACE1, BACE2, MAPt), neuroinflammation (IL-6, TNF-α) markers in neurotoxic rats. Docking studies of 8 compounds demonstrated negative binding energies for cholinesterase and ß-secretase indicating high affinity for target enzymes in AD. Test results were corroborated by the improvement of cellular tissue architecture of brain cortex in AD rats. CONCLUSION: Synergistic action of genistin, quercetin-3-D-galactoside, 9,12,15-octadecatrienoic-acid methyl-ester, phytol, retinal, stigmasterol, n-hexadecanoic acid, ß-sitosterol in GRHA restores memory-deficits via attenuation of cholinesterase, ß-secretase, MAPt level and inhibition of oxidative-stress imparts inflammation in AD.

Isobavachalcone ameliorates cognitive deficits, and Aß and tau pathologies in triple-transgenic mice with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects 50 million people worldwide. The current medicines have modest benefits in preventing or curing AD. Thus, it is urgent to discover drugs with the potential to change the progression of the disease. The primary clinical symptoms are memory loss and anxiety, while the critical pathological characteristics are Aß plaques and hyperphosphorylated tau tangles. In this study, isobavachalcone (ISO), isolated from Psoralea corylifolia, was administered to 3×Tg-AD mice. It has been shown that this compound could significantly improve anxiety, memory and recognition deficits in the AD mice, attenuate the accumulation of Aß oligomers, reduce the hyperphosphorylation of tau, and prevent the production of tau filaments. The metabolomic analysis implicates that the most probable pathways affected by ISO were bile secretion, tyrosine metabolism, and purine metabolism. In summary, ISO possesses the potential for further development as a drug candidate for AD.

Membrane interaction and disulphide-bridge formation in the unconventional secretion of Tau.

Misfolded, pathological tau protein propagates from cell to cell causing neuronal degeneration in Alzheimer's disease and other tauopathies. The molecular mechanisms of this process have remained elusive. Unconventional secretion of tau takes place via several different routes, including direct penetration through the plasma membrane. Here, we show that tau secretion requires membrane interaction via disulphide bridge formation. Mutating residues that reduce tau interaction with membranes or formation of disulphide bridges decrease both tau secretion from cells, and penetration through artificial lipid membranes. Our results demonstrate that tau is indeed able to penetrate protein-free membranes in a process independent of active cellular processes and that both membrane interaction and disulphide bridge formation are needed for this process. QUARK-based de novo modelling of the second and third microtubule-binding repeat domains (MTBDs), in which the two cysteine residues of 4R isoforms of tau are located, supports the concept that this region of tau could form transient amphipathic helices for membrane interaction.

Identification of cis-acting determinants mediating the unconventional secretion of tau.

The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer's disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau.

Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes.

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Pre-Clinical Neuroprotective Evidences and Plausible Mechanisms of Sulforaphane in Alzheimer's Disease.

Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-ß, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.

Yuan­zhi­san inhibits tau protein aggregation in an Aß1­40­induced Alzheimer's disease rat model via the ubiquitin­proteasome system.

Yuan­zhi­san (YZS) is a classic type of Traditional Chinese Medicine, which has been reported to aid in the treatment of Alzheimer's disease (AD). The present study aimed to investigate the effects of YZS on tau protein aggregation, a hallmark of AD pathology, and its possible mechanisms. The results demonstrated that YZS improved learning and memory abilities, and decreased the severity of AD pathology in ß­amyloid (Aß1­40)­induced AD rats. Moreover, YZS administration inhibited the hyperphosphorylation of tau protein at Ser199 and Thr231 sites. Several vital enzymes in the ubiquitin­proteasome system (UPS), including ubiquitin­activating enzyme E1a/b, ubiquitin­conjugating enzyme E2a, carboxyl terminus of Hsc70­interacting protein, ubiquitin C­236 terminal hydrolase L1 and 26S proteasome, were all significantly downregulated in AD rats, which indicated an impaired enzymatic cascade in the UPS. In addition, it was identified that YZS treatment partly increased the expression levels of these enzymes in the brains of AD rats. In conclusion, the present results suggested that YZS could effectively suppress the hyperphosphorylation of tau proteins, which may be partially associated with its beneficial role in restoring functionality of the UPS.

Flavanol-rich lychee fruit extract substantially reduces progressive cognitive and molecular deficits in a triple-transgenic animal model of Alzheimer disease.

Effective treatment to prevent or arrest the advance of Alzheimer disease (AD) has yet to be discovered. We investigated whether OligonolR, an FDA-approved flavanol-rich extract prepared from lychee fruit and green tea, exerted beneficial effects relevant to AD in a triple transgenic male mouse model of AD (3×Tg-AD). At 9 months of age, untreated 3×Tg-AD mice vs. wild-type (WT) controls displayed cognitive deficits in behavioral assays and, at 12 months, elevated levels of hippocampal amyloid beta-protein (Aß), amyloid precursor protein (APP), tau phosphorylation, and pro-inflammatory cytokines. 3×Tg-AD mice given Oligonol showed fewer cognitive deficits and attenuated pathological indices at 12 months. Oligonol treatment of 3×Tg-AD mice modulated expression of some critical brain proteins that involve multiple pathways relevant to mitochondrial dysfunction, proteasomal failure, endoplasmic reticulum (ER) stress and synaptic impairment. Together, these results demonstrate that continuous Oligonol treatment attenuates AD-like pathology and cognitive impairment of 3×Tg-AD mice and set the stage for clinical trials of this flavanol-rich plant extract in patients with early AD.

Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort.

OBJECTIVE: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI). METHODS: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception. RESULTS: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum. CONCLUSION: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.

Chronic cannabidiol (CBD) treatment did not exhibit beneficial effects in 4-month-old male TAU58/2 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, motor impairments, and accumulation of hallmark proteins, amyloid-beta (Aß) and tau. Traditionally, transgenic mouse models for AD have focused on Aß pathology, however, recently a number of tauopathy transgenic models have been developed, including the TAU58/2 transgenic model. Cannabidiol (CBD), a non-toxic constituent of the Cannabis sativa plant, has been shown to prevent and reverse cognitive deficits in Aß transgenic mouse models of AD. Importantly, the therapeutic properties of CBD on the behavioural phenotype of tauopathy mouse models have not been investigated. We assessed the impact of chronic CBD treatment (i.e. 50 mg/kg CBD i.p. administration starting 3 weeks prior to behavioural assessments) on disease-relevant behaviours of 4-month-old TAU58/2 transgenic males in paradigms for anxiety, motor functions, and cognition. TAU58/2 transgenic males demonstrated reduced body weight, anxiety and impaired motor functions. Furthermore, they demonstrated increased freezing in fear conditioning compared to wild type-like animals. Interestingly, both sociability and social recognition memory were intact in AD transgenic mice. Chronic CBD treatment did not affect behavioural changes in transgenic males. In summary, 4-month-old TAU58/2 transgenic males exhibited no deficits in social recognition memory, suggesting that motor deficits and changes in anxiety at this age do not impact on social domains. The moderate increase in fear-associated memory needs further investigation but could be related to differences in fear extinction. Future investigations will need to clarify CBD's therapeutic potential for reversing motor deficits in TAU58/2 transgenic mice by considering alternative CBD treatment designs including changed CBD dosing.

Prediction of human tau 3D structure, and interplay between O-ß-GlcNAc and phosphorylation modifications in Alzheimer's disease: C. elegans as a suitable model to study these interactions in vivo.

Tau protein regulates, maintains and stabilizes microtubule assembly under normal physiological conditions. In certain pathological circumstances, tau is post-translationally modified predominantly via phosphorylation and glycosylation. Hyper-phosphorylation of tau in Alzheimer's disease (AD) resulted in aggregated neurofibrillary tangles (NFTs) formation. Unfortunately, absence of tau 3D structure makes difficult to understand exact mechanism involved in tau pathology. Here by using ab-initio modelling, we predicted a tau 3D structure that not only explains its binding with microtubules but also elucidates NFTs formation. O-linked ß-N-acetylglucosaminylation (O-ß-GlcNAc) is thought to regulate tau phosphorylation on single or proximal Ser/Thr residues (called as Yin-Yang sites). In this study, we not only validate the previously described three-serine residues (208, 238 and 400) as Yin-Yang sites but also predicted 22 more possible Ser/Thr O-glycosylation sites. Among them seventeen residues were predicted as possible Yin-Yang sites and are proposed to mediate NFT formation in AD. These predicted Yin-Yang sites may act as attractive therapeutic targets for the drug development in AD. Predicted 3D structure of tau441 was highly accessible for phosphorylation and hyperphosphorylation, and showed higher surface accessibility for interplay between O-ß-GlcNAc and phosphorylation modifications. Kinases and phosphatases involved in tau phosphorylation are conserved in human and other organisms. Homology modelling revealed conserved catalytic domain for both human and C. elegans O-GlcNAc transferase (OGT), suggesting that transgenic C. elegans expressing human tau may be a suitable model system to study these modifications.

Pine Bark Polyphenolic Extract Attenuates Amyloid-ß and Tau Misfolding in a Model System of Alzheimer's Disease Neuropathology.

Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer's disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-ß protein (Aß). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aß1-40 and Aß1-42, but also tau in vitro. Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O-ß-Glucuronide, Me-(±)-C-O-ß-glucuronide, EC-O-ß-glucuronide, and (±)-C-O-ß-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD.