Alzheimer's Disease R&D Review
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Alzheimer's Disease R&D Review
A review of the Solanezumab (Lilly), Gantenerumab (Roche) the 2  beta amyloid monoclonal antibodies  in Phase III trials and other potential targets is provided. The failure of Bapineuzumab in Phase III trials in 2012 puta question mark on the validity of beta amyloid hypothesis. Bapineuzumab is a fully humanized monoclonal antibody which targets beta amyloid protein involved in Alzheimer's Disease. There are 26 million patients in the world, half in Asia and the rest in N America/Europe with AD.
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Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review"

Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review" | Alzheimer's Disease R&D Review | Scoop.it
Krishan Maggon published version 237 of a knol titled: "Bapineuzumab (Pfizer, J&J, Elan) Review"...
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Researchers unite in quest for ‘standard model’ of the brain

Researchers unite in quest for ‘standard model’ of the brain | Alzheimer's Disease R&D Review | Scoop.it
Modelled on big physics projects, the International Brain Lab will bring together some of the world’s pre-eminent neuroscientists to probe a single behaviour.
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Synthesis, characterization, X-ray crystal structures of heterocyclic Schiff base compounds and in vitro cholinesterase inhibition and anticancer activity

Synthesis, characterization, X-ray crystal structures of heterocyclic Schiff base compounds and in vitro cholinesterase inhibition and anticancer activity | Alzheimer's Disease R&D Review | Scoop.it
Highlights • Four new Schiff base compounds were synthesized and fully characterized. • Compound 1 showed good BuChE enzyme inhibitory activities (IC50 1.45 ± 0.09 μM). • Compound 4 showed antiproliferative effect (IC50 21.1 μM) against MCF-7 (SI 3.3). • Compound 2 exhibited IC50 34 μM against HCT 116.
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ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy | Alzheimer's Disease R&D Review | Scoop.it
APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.
Krishan Maggon 's insight:
Nature (2017) doi:10.1038/nature24016
Published online 20 September 2017 Article tools
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Integrating Stem Cells into Functional Neural Networks - AZ Neuro Mod

Integrating Stem Cells into Functional Neural Networks - AZ Neuro Mod | Alzheimer's Disease R&D Review | Scoop.it
The inherent potential of stem cells to engender any cellular form and function drives the field of regenerative medicine. In recent years, stem cell research has witnessed prolific growth particularly in disease-modeling, drug discovery and patient-specific cell therapy. A major challenge in stem cell-mediated therapy is to understand and promote integration of transplanted stem cells…
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TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant

TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant | Alzheimer's Disease R&D Review | Scoop.it
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2‐expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N‐terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157‐S158 peptide bond for both wild‐type and H157Y human TREM2 and for the wild‐type murine orthologue. Crucially, we also show that the Alzheimer's disease‐associated H157Y TREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat‐ and ADAM10‐siRNA‐independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases.

See also: [K Schlepckow et al ][1]

![][2]

Sequence variation in the microglial receptor protein TREM2 is linked to risk for Alzheimer's disease. The disease‐linked H157Y variant of TREM2 is found to affect the sheddase site and accelerates proteolytic loss of TREM2 from the cell surface.

[1]: https://doi.org/10.15252/emmm.201707672
[2]: /embed/graphic-1.gif
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Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors

Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors | Alzheimer's Disease R&D Review | Scoop.it
Surface diffusion of AMPA receptors, from extra-synaptic to synaptic sites at the plasma membrane, is essential for full long-term potentiation in hippocampal neurons and for fear conditioning in living mice.
Krishan Maggon 's insight:
Nature (2017) doi:10.1038/nature23658
Published online 13 September 2017
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Cell Replacement Therapy For Parkinson’s Disease And The Future Of The Brain

Cell Replacement Therapy For Parkinson’s Disease And The Future Of The Brain | Alzheimer's Disease R&D Review | Scoop.it
Cell Replacement Therapy For Parkinson's Disease
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Loss of brain inter-frequency hubs in Alzheimer's disease

Loss of brain inter-frequency hubs in Alzheimer's disease | Alzheimer's Disease R&D Review | Scoop.it

Article


Alzheimer’s disease (AD) causes alterations of brain network structure and function. The latter consists of connectivity changes between oscillatory processes at different frequency channels. We proposed a multi-layer network approach to analyze multiple-frequency brain networks inferred from magnetoencephalographic recordings during resting-states in AD subjects and age-matched controls. Main results showed that brain networks tend to facilitate information propagation across different frequencies, as measured by the multi-participation coefficient (MPC). However, regional connectivity in AD subjects was abnormally distributed across frequency bands as compared to controls, causing significant decreases of MPC. This effect was mainly localized in association areas and in the cingulate cortex, which acted, in the healthy group, as a true inter-frequency hub. MPC values significantly correlated with memory impairment of AD subjects, as measured by the total recall score. Most predictive regions belonged to components of the default-mode network that are typically affected by atrophy, metabolism disruption and amyloid-β deposition. We evaluated the diagnostic power of the MPC and we showed that it led to increased classification accuracy (78.39%) and sensitivity (91.11%). These findings shed new light on the brain functional alterations underlying AD and provide analytical tools for identifying multi-frequency neural mechanisms of brain diseases.

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Mechanisms of Connectome Development

Mechanisms of Connectome Development | Alzheimer's Disease R&D Review | Scoop.it
At the centenary of D’Arcy Thompson’s seminal work ‘On Growth and Form’, pioneering
the description of principles of morphological changes during development and evolution,
recent experimental advances allow us to study change in anatomical brain networks.
Here, we outline potential principles for connectome development. We will describe
recent results on how spatial and temporal factors shape connectome development in
health and disease. Understanding the developmental origins of brain diseases in individuals
will be crucial for deciding on personalized treatment options.
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Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation

Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation | Alzheimer's Disease R&D Review | Scoop.it
Thomas et al. used human pluripotent stem cells to dissect the contribution of neurons
and glia to the neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). They
found that mutant cells accumulate retroviral-like extrachromosomal nucleic acids
that trigger a neurotoxic response, and they suggest that anti-retrovirals could potentially
provide therapy for this disease.
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Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche

Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche | Alzheimer's Disease R&D Review | Scoop.it
Neural stem cells (NSCs) are a heterogeneous population of cells that generate new
neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic
neurons control activation of a subset of NSCs in response to feeding, providing insights
into how physiological cues may influence stem cell activation.
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The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome

The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome | Alzheimer's Disease R&D Review | Scoop.it
Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer’s disease proteins and negatively regulates amyloid-β peptide levels. Here, we hypothesized that RER1 might also play an important role in retention/retrieval of αSyn and mediate levels. We expressed RER1 and a C-terminal mutant RER1Δ25, which lacks the ER retention/retrieval function, in HEK293 and H4 neuroglioma cells. RER1 overexpression significantly decreased levels of both wild type and A30P, A53T, and E46K disease causal mutants of αSyn, whereas the RER1Δ25 mutant had a significantly attenuated effect on αSyn. RER1 effects were specific to αSyn and had little to no effect on either βSyn or the Δ71–82 αSyn mutant, which both lack the NAC domain sequence critical for synuclein fibrillization. Tests with proteasomal and macroautophagy inhibitors further demonstrate that RER1 effects on αSyn are primarily mediated through the ubiquitin-proteasome system. RER1 also appears to interact with the ubiquitin ligase NEDD4. RER1 in human diseased brain tissues co-localizes with αSyn-positive Lewy bodies. Together, these findings provide evidence that RER1 is a novel and potential important mediator of elevated αSyn levels. Further investigation of the mechanism of RER1 and downstream effectors on αSyn may yield novel therapeutic targets for modulation in Parkinson disease and related synucleinopathies.
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Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders

Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders | Alzheimer's Disease R&D Review | Scoop.it
The final stage of brain development is associated with the generation and maturation of neuronal synapses. However, the same period is also associated with a peak in synapse elimination — a process known as synaptic pruning — that has been proposed to be crucial for the maturation of remaining synaptic connections. Recent studies have pointed to a key role for glial cells in synaptic pruning in various parts of the nervous system and have identified a set of critical signalling pathways between glia and neurons. At the same time, brain imaging and post-mortem anatomical studies suggest that insufficient or excessive synaptic pruning may underlie several neurodevelopmental disorders, including autism, schizophrenia and epilepsy. Here, we review current data on the cellular, physiological and molecular mechanisms of glial-cell-dependent synaptic pruning and outline their potential contribution to neurodevelopmental disorders.
Krishan Maggon 's insight:
Nature Reviews Neuroscience (2017) doi:10.1038/nrn.2017.110 Published online 21 September 2017
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Axonal synapse sorting in medial entorhinal cortex

Axonal synapse sorting in medial entorhinal cortex | Alzheimer's Disease R&D Review | Scoop.it
Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges.
Krishan Maggon 's insight:
Nature (2017) doi:10.1038/nature24005 
Published online 20 September 2017
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Abnormal amyloid β42 expression and increased oxidative stress in plasma of CKD patients with cognitive dysfunction: A small scale case control study comparison with Alzheimer's disease

Abnormal amyloid β42 expression and increased oxidative stress in plasma of CKD patients with cognitive dysfunction: A small scale case control study comparison with Alzheimer's disease | Alzheimer's Disease R&D Review | Scoop.it
Highlights • Cognitive dysfunction has been increasingly recognized in chronic kidney disease (CKD) patients. • The major component of plaques is the amyloid β peptide released from proteolytic cleavage of amyloid precursor protein. • Plasma Aβ has been a focus of the growing literature on blood based biomarkers for cognitive dysfunction. • Oxidative stress is prevalent in CKD and it plays an important role in cognitive dysfunction. • Increased oxidative stress leads to cause cleavage of APP and Aβ production.
Krishan Maggon 's insight:
BBA Clinical Volume 8, December 2017, Pages 20-27
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Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift | Alzheimer's Disease R&D Review | Scoop.it
Jassam et al. review advances in the role of neuroinflammation in traumatic brain
injury (TBI) in a chronological and compartment-based manner. The authors propose
a new paradigm that moves away from the existing M1/M2 approach to classify microglia
in TBI toward a proteomics- and transcriptomics-based approach.
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Schizophrenia and Memory Deficits: Solving the Mystery Behind a Most Stubborn Symptom

Schizophrenia and Memory Deficits: Solving the Mystery Behind a Most Stubborn Symptom | Alzheimer's Disease R&D Review | Scoop.it
New study in mice reveals biological origins of a core symptom of schizophrenia; offers promising new avenues for drug intervention and treatment.
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An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function | Alzheimer's Disease R&D Review | Scoop.it
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)‐like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2‐dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C‐terminal to histidine 157, a position where an AD‐associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig‐like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full‐length TREM2 and lowers TREM2‐dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2.

See also: [P Thornton et al ][1]

![][2]

The triggering receptor expressed on myeloid cells 2 (TREM2) is shed on the cell surface by ADAM10 and ADAM17 between histidine 157 and serine 158, a site where the AD associated p.H157Y variant was found. p.H157Y increases shedding and impairs phagocytic function by lowering cell surface TREM2.

[1]: https://doi.org/10.15252/emmm.201707673
[2]: /embed/graphic-1.gif
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Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity

Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity | Alzheimer's Disease R&D Review | Scoop.it
Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson’s Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35–55 (MOG-35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies.
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Microglia emerge as central players in brain disease

Microglia emerge as central players in brain disease | Alzheimer's Disease R&D Review | Scoop.it
There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.
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Krishan Maggon 's curator insight, September 11, 11:33 AM
Nature Medicine 23, 1018–1027 (2017) doi:10.1038/nm.4397
Published online 08 September 2017
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Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus

Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus | Alzheimer's Disease R&D Review | Scoop.it
Kim et al. show that inhibitory basal ganglia inputs yield excitatory motor signals
in the thalamus and, in excess, promote PD-like motor abnormalities. These suggest
that the role of inhibitory basal ganglia circuits should be re-evaluated with consideration
of their ability to induce excitatory signals at post-synaptic targets.
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New Non-Embryonic Stem Cell Study Shows Progress with Parkinson’s Disease | Charlotte Lozier Institute

New Non-Embryonic Stem Cell Study Shows Progress with Parkinson’s Disease | Charlotte Lozier Institute | Alzheimer's Disease R&D Review | Scoop.it
Ever since human embryonic stem cells (hESCs) were first successfully grown in the lab in 1998, Parkinson’s Disease has featured prominently as one of the major diseases that such cells would supposedly eliminate.   The actor Michael J.
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The physical dimensions of amyloid aggregates control their infective potential as prion particles

The physical dimensions of amyloid aggregates control their infective potential as prion particles | Alzheimer's Disease R&D Review | Scoop.it
Size threshold and suprastructure formation are key parameters that control the infective potential of amyloid fibrils as prion particles.
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A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity

A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity | Alzheimer's Disease R&D Review | Scoop.it
Controlled balance between proliferation and quiescence of neural stem/progenitor
cells (NSPCs) is required for lifelong neurogenesis. Knobloch et al. identify a metabolic
shift in fatty acid oxidation (FAO) that governs the proliferation of NSPCs. Further,
their data suggest an instructive role for FAO in regulating NSPC activity. Thus,
Knobloch et al. identify FAO as a key metabolic pathway to regulate NSPC activity.
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Structural studies of amyloid-β peptides: Unlocking the mechanism of aggregation and the associated toxicity

Structural studies of amyloid-β peptides: Unlocking the mechanism of aggregation and the associated toxicity | Alzheimer's Disease R&D Review | Scoop.it
Abstract Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. Formation of amyloid plaques consisting of amyloid-β peptides (Aβ) is one of the hallmarks of AD. Several lines of evidence have shown a correlation between the Aβ aggregation and the disease development. Extensive research has been conducted with the aim to reveal the structures of the neurotoxic Aβ aggregates. However, the exact structure of pathological aggregates and mechanism of the disease still remains elusive due to complexity of the occurring processes and instability of various disease-relevant Aβ species. In this article we review up-to-date structural knowledge about amyloid-β peptides, focusing on data acquired using solution and solid state NMR techniques. Furthermore, we discuss implications from these structural studies on the mechanisms of aggregation and neurotoxicity. 

 Keywords Alzheimer's diseaseAmyloid-β peptideAmyloid structureAggregation mechanismNeurotoxicity
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