I have a Ph.D. in Medicinal Chemistry. I am fascinated by the complexities of Alzheimer's disease.
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.
Abstract: Alz-50 is a monoclonal antibody directed against an antigen present in Alzheimer's disease. Unlike conventional pathological stains that reveal only neurons with neurofibrillary tangles (NFTs), Alz-50 recognizes neurons that contain NFTs and additional neurons that do not. Our investigation of the topographical distribution of both NFT-containing and non-NFT-containing neurons recognized by Alz-50 reveals that they are both found primarily in certain cytoarchitectural areas and lamina that have been established as consistent sites for NFT pathology. Some of the neurons recognized by Alz-50 appear histopathologically normal. We suggest that Alz-50 recognizes an antigen in neurons that both precedes and accompanies NFT formation. Thus, it may mark a point early in cellular pathology before irreversible cytoskeletal and degenerative changes occur.
Pub.: 01 Apr '88, Pinned: 13 Apr '17
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
Abstract: The invention relates to antibodies that bind cross-linked amyloid β oligomers, and methods for using such antibodies for diagnosis and treatment of Alzheimer's disease.
Pub.: 07 Jun '11, Pinned: 13 Apr '17
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
Abstract: The neuropathology associated with Alzheimer's disease (AD) is characterized by the presence of extracellularly neuritic plaques, intracellularly neurofibrillary tangles and the loss of basal forebrain cholinergic neurons. The neuritic plaque is composed of a core of amyloid-beta peptide (Abeta) while the neurofibrillary tangles contain phosphorylated tau protein, and, as such, both Abeta and tau are important molecules associated with AD. In healthy human bodies, clearance mechanisms for Abeta are available; yet if clearance fails, Abeta accumulates, increasing the risk of neurotoxicity in the brain. Tau, one of the main microtubule-associated proteins, will be hyperphosphorylated and lose the ability to bind microtubules when the homeostasis of phosphorylation and dephosphorylation is disturbed in neurons. Accumulated Abeta and hyperphosphorylated tau are thought to be coexistent. Research on the pathological changes in AD indicates that accumulated Abeta in vivo may initiate the hyperphosphorylation of tau. Also, the signal transduction pathways of tau hyperphosphorylation may be related to accumulated Abeta. In this review, we will discuss how Abeta accumulates, how tau protein is hyperphosphorylated, and how accumulated Abeta initiates hyperphosphorylation of tau protein in AD.
Pub.: 23 Jan '09, Pinned: 13 Apr '17
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
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
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
Abstract: Microglia and astrocytes have been considered until now as cells with very distinct identities. Here, we assessed the heterogeneity within microglia/monocyte cell population in mouse hippocampus and determined their response to injury, by using single-cell gene expression profiling of cells isolated from uninjured and deafferented hippocampus. We found that in individual cells, microglial markers Cx3cr1, Aif1, Itgam, and Cd68 were co-expressed. Interestingly, injury led to the co-expression of the astrocyte marker Gfap in a subpopulation of Cx3cr1-expressing cells from both the injured and contralesional hippocampus. Cells co-expressing astrocyte and microglia markers were also detected in the in vitro LPS activation/injury model and in sections from human brain affected by stroke, Alzheimer's disease, and Lewy body dementia. Our findings indicate that injury and chronic neurodegeneration lead to the appearance of cells that share molecular characteristics of both microglia and astrocytes, 2 cell types with distinct embryologic origin and function.
Pub.: 12 Apr '17, Pinned: 13 Apr '17
Abstract: Neuronal cell injury, as a consequence of acute or chronic neurological trauma, is a significant cause of mortality around the world. On a molecular level, the condition is characterized by widespread cell death and poor regeneration, which can result in severe morbidity in survivors. Potential therapeutics are of major interest, with a promising candidate being brain-derived neurotrophic factor (BDNF), a ubiquitous agent in the brain which has been associated with neural development and may facilitate protective and regenerative effects following injury. This review summarizes the available information on the potential benefits of BDNF and the molecular mechanisms involved in several pathological conditions, including hypoxic brain injury, stroke, Alzheimer's disease and Parkinson's disease. It further explores the methods in which BDNF can be applied in clinical and therapeutic settings, and the potential challenges to overcome.
Pub.: 12 Apr '17, Pinned: 13 Apr '17
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
Abstract: The effect of citrate-stabilized gold nanoparticles (AuNPs) on the secondary structure of an artificial β-sheet-forming cationic peptide has been studied. The AuNPs inhibited β-sheet formation and led to fragmented fibrils and spherical oligomers with assembled AuNPs on their surface. Besides this structural change, the functional properties of the peptide are also different. Whereas the peptide was unable to act as a vector for gene delivery, formation of a complex with AuNPs allowed successful gene delivery into cells.
Pub.: 10 Apr '17, Pinned: 13 Apr '17
Abstract: To describe the burden of disease in the Australian residential aged care population.Cross-sectional analysis of Aged Care Funding Instrument data.Dementia (48%), depression (22.5%) and arthritis (14.2%) were the most prevalent chronic diseases in this population. Unclassified conditions such as falls, pain and urinary incontinence were also significant burdens in this population (17.1%). Circulatory, musculoskeletal and unclassified conditions were the most prevalent comorbidities across all common medical groups. Dementia and depression were the most common comorbid mental health conditions across all medical groups.The challenges for evaluating clinical care in Australian residential aged care are many. Delivering good clinical care should be a priority for aged care providers given the high burden of chronic disease and comorbidity. An informative starting point could be to target management of the most prevalent and burdensome conditions and comorbidities.
Pub.: 11 Apr '17, Pinned: 13 Apr '17