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CURATOR

I have a Ph.D. in Medicinal Chemistry. I am fascinated by the complexities of Alzheimer's disease.

PINBOARD SUMMARY

Follow the latest developments in new drugs and treatments for Alzheimer's disease

Although some symptomatic treatments are available, Alzheimer's disease is an irreversible neurodegenerative disease which leads to dementia and ultimately death. We need to fight this disease so that we can live longer and better lives.

13 ITEMS PINNED

Amelioration of amyloid load by anti-Abeta single-chain antibody in Alzheimer mouse model.

Abstract: Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid beta-peptide (Abeta) prevented or reduced Abeta deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Abeta, however, was halted due to brain inflammation, presumably induced by a toxic Abeta, T-cell- and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Abeta vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Abeta also induced clearance of amyloid plaques in the model mice, injection of humanized Abeta antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Abeta immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Abeta as well as amyloid plaques in the brain. The scFv inhibited Abeta amyloid fibril formation and Abeta-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Abeta deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Abeta may be useful to treat AD patients without eliciting brain inflammation.

Pub.: 25 Apr '06, Pinned: 13 Apr '17

Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.

Abstract: Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

Pub.: 18 Feb '15, Pinned: 13 Apr '17

Neuritic pathology and dementia in Alzheimer's disease.

Abstract: Previous studies of Alzheimer's disease (AD) have correlated the severity of dementia with either the number of senile plaques or neurofibrillary tangles. We used antibodies raised against amyloid beta/A4 protein of senile plaque cores and tau protein as well as thioflavine S and the Campbell-Switzer modification of the Hicks silver method to examine the hippocampal formation and five neocortical regions from 22 nondemented elderly control subjects and 34 demented patients with cerebral senile plaques and neurofibrillary tangles, without complicating disease processes. Ten control subjects (46%) had no beta/A4 protein deposition. Twelve control subjects (54%) had widespread beta/A4 protein deposition but no neocortical neuritic pathology. Of the 34 patients with AD-type changes, 27 (79%) had widespread senile plaques and neurofibrillary tangles, while 7 (21%) had neocortical senile plaques with few neurofibrillary tangles. All demented patients had widespread beta/A4 protein deposition and neocortical tau-immunoreactive, Hicks silver-positive dystrophic neurites. The neurites were found both free in the neuropil as well as surrounding senile plaques. Quantitative analysis showed that dystrophic neurites were significantly increased in patients with AD compared with control subjects and the number of dystrophic neurites and neurofibrillary tangles correlated with the clinical severity of dementia. Widespread cerebral beta/A4 protein deposition may be necessary but by itself is insufficient for the development of dementia in AD.

Pub.: 01 Aug '91, Pinned: 13 Apr '17

Targeting tau protein in Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is characterized histopathologically by numerous neurons with neurofibrillary tangles and neuritic (senile) amyloid-beta (Abeta) plaques, and clinically by progressive dementia. Although Abeta is the primary trigger of AD according to the amyloid cascade hypothesis, neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of this disease. Furthermore, while approximately 30% of normal aged individuals have as much compact plaque burden in the neocortex as is seen in typical cases of AD, in several tauopathies, such as cortical basal degeneration and Pick's disease, neurofibrillary degeneration of abnormally hyperphosphorylated tau in the absence of Abeta plaques is associated with dementia. To date, all AD clinical trials based on Abeta as a therapeutic target have failed. In addition to the clinical pathological correlation of neurofibrillary degeneration with dementia in AD and related tauopathies, increasing evidence from in vitro and in vivo studies in experimental animal models provides a compelling case for this lesion as a promising therapeutic target. A number of rational approaches to inhibiting neurofibrillary degeneration include inhibition of one or more tau protein kinases, such as glycogen synthase kinase-3beta and cyclin-dependent protein kinase 5, activation of the major tau phosphatase protein phosphatase-2A, elevation of beta-N-acetylglucosamine modification of tau through inhibition of beta-N-acetylglucosaminidase or increase in brain glucose uptake, and promotion of the clearance of the abnormally hyperphosphorylated tau by autophagy or the ubiquitin proteasome system.

Pub.: 11 May '10, Pinned: 13 Apr '17

Transport of Curcumin Derivatives in Caco-2 Cell Monolayers.

Abstract: Curcumin (Cur) is a strong natural antioxidant, who can prevent multiple diseases such as anti-cancer, anti-inflammatory, have a resistance to alzheimer's disease and various malignant diseases. But it has poor oral bioavailability due to its poor aqueous solubility, as well as instability. While its novel derivatives (CB and FE), showed better anti-tumor activity, better anti-oxidant activity and better stability than the original drug (Cur). The aim of this study was to study the intestinal transport of Cur, CB and FE using an in vitro Caco-2 cell monolayer model. The results showed that Cur had a lower permeability coefficient (1.13 × 10(-6) ± 0.11 × 10(-6) cm/s) for apical-to-basolated (AP-BL) transport at 25 μM, while the transport rate for AP to BL flux of CB (3.18 × 10(-6) ± 0.31 × 10(-6) cm/s) and FE (5.28 × 10(-6) ± 0.83 × 10(-6) cm/s) were significantly greater than that of Cur. The efflux ratio (ER) value at the concentrate of 25 μM was 1.31 for Cur, 1.26 for CB and 1.33 for FE, suggesting there was no active efflux involved in the translocation across the Caco-2 cell monolayers for the three compounds. Furthermore, the transport flux of CB and FE was in a concentration dependent manner, suggesting the intestinal transport mechanism in them was passive transport. In summary, the results demonstrated that both the intestinal permeability of CB and FE across Caco-2 cell monolayers was significantly improved compare to Cur. Thus they might show a higher oral bioavailability in vivo, and show the potential application in clinic or nutraceutical.

Pub.: 12 Apr '17, Pinned: 13 Apr '17

Caenorhabditis elegans as a model for exploring the efficacy of synthesized organoruthenium complexes for aging and Alzheimer's disease a neurodegenerative disorder: A systematic approach

Abstract: The current article deals with the preparation and characterisation of new organoruthenium(II) complexes, namely [RuCp(Dea-Sal-tsc)(PPh3)] (1), [RuCp(Dea-Sal-mtsc)(PPh3)] (2), [RuCp(Dea-Sal-etsc)(PPh3)] (3) and [RuCp(Dea-Sal-ptsc)(PPh3)] (4). The new ruthenium(II) complexes were characterized by various analytical, spectral techniques. The structure of the ligand [H2-Dea-Sal-tsc] and the complex [RuCp(Dea-Sal-tsc)(PPh3)] (1) were confirmed by X-ray crystallography. The complexes (1–4) were used to study the toxicity, stress resistance, aging and neuro-protective effects by taking Caenorhabditis elegans as model. In vitro free radical scavenging activity was performed by DPPH free radical scavenging assay, the complexes (1–4) exhibited highest scavenging activity than standard Vitamin C (IC50 = 5.28 ± 0.10). The lifespan has increased over 22.4% in mev-1 mutant worms treated with complex 4. The complex 4 triggered the DAF-16 nuclear localization, increases sod-3 expression and reduced amyloid (Aβ) protein induced paralysis were observed. In the present study we confirmed that oxidative stress resistance of N2 and lifespan extension of mev-1 mutant which showed the potential ROS scavenging activity of complex 4. The results also confirmed the effective anti-aging potential of ruthenium complex 4 which may be developed as a therapeutic drug for the prevention of aging and age related neurodegenerative diseases. Further studies are required to find out the exact action of complex 4 on higher model.

Pub.: 14 Mar '17, Pinned: 13 Apr '17