Structure and function of amyloid in Alzheimer's disease

Morgan, Carlos; Colombres, Marcela; Núñez, Marco T.; Inestrosa, Nibaldo C.

doi:10.1016/j.pneurobio.2004.10.004

Cited by 124 publications

(123 citation statements)

References 291 publications

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“…1 The neurotoxicity of the amyloid-b-peptide (Ab) is highly dependent on its conformation, quaternary structure and morphology of the bundles formed. [2][3][4] It has been proposed that Ab aggregation would require inherent depolymerization mechanisms in order to explain the morphology and the stable size of the senile plaques observed in AD, 5 which indicates that amyloidogenesis is a continuous process of polymerization and depolymerization. 6 As Ab is toxic to neurons, 7 the main targets for therapeutic intervention of the Ab cascade include the inhibition of Ab production, the inhibition of Ab aggregation and fibril formation, in addition to the inhibition of the consequent inflammatory responses caused by the Ab deposition.…”

Section: Introductionmentioning

confidence: 99%

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Dinamarca¹,

Cerpa²,

Garrido

et al. 2006

Mol Psychiatry

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The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid b-peptide (Ab). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Ab-induced spatial memory impairments and on Ab neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Ab-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Ab oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Ab aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

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Section: Introductionmentioning

confidence: 99%

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Dinamarca¹,

Cerpa²,

Garrido

et al. 2006

Mol Psychiatry

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“…A␤ peptide acquires neurotoxic properties when it forms homo-oligomeric species (17) or heterooligomeric species with molecules associated with mature senile plaques and/or A␤ deposits in cerebral blood vessels (18), such as the enzyme acetylcholinesterase (AChE), a protein that forms stable A␤⅐AChE complexes (19), which are more neurotoxic than A␤ alone (20).…”

mentioning

confidence: 99%

Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

Santos

Quintanilla²,

Toro

et al. 2005

Journal of Biological Chemistry

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Alzheimer disease is a neurodegenerative process that leads to severe cognitive impairment as a consequence of selective death of neuronal populations. The molecular pathogenesis of Alzheimer disease involves the participation of the ␤-amyloid peptide (A␤) and oxidative stress. We report here that peroxisomal proliferation attenuated A␤-dependent toxicity in hippocampal neurons. Pretreatment with Wy-14.463 (Wy), a peroxisome proliferator, prevent the neuronal cell death and neuritic network loss induced by the A␤ peptide. Moreover, the hippocampal neurons treated with this compound, showed an increase in the number of peroxisomes, with a concomitant increase in catalase activity. Additionally, we evaluate the Wy protective effect on ␤-catenin levels, production of intracellular reactive oxygen species, cytoplasmic calcium uptake, and mitochondrial potential in hippocampal neurons exposed to H 2 O 2 and A␤ peptide. Results show that the peroxisomal proliferation prevents ␤-catenin degradation, reactive oxygen species production, cytoplasmic calcium increase, and changes in mitochondrial viability. Our data suggest, for the first time, a direct link between peroxisomal proliferation and neuroprotection from A␤-induced degenerative changes.Peroxisomes are subcellular organelles found in most animal cells that perform diverse metabolic functions, including detoxification of reactive oxygen species (ROS) 2 through their matrix enzyme catalase (1-3) and regulation of the oxidative balance and fatty acid oxidation (4 -6). Peroxisomes are present in the cell bodies, dendrites, and presynaptic axon terminals of neuronal cells (7,8) as well as in growing neurites (9). Tau overexpression inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites (10), and it has been suggested that a loss of peroxisomes apparently makes neurons more vulnerable to oxidative stress (10). Peroxisome proliferators (PPs) are a class of structurally dissimilar industrial and pharmaceutical chemicals that were originally identified as inducers of peroxisome proliferation in rat and mouse hepatocytes (11,12). Several PPs have shown to bind to peroxisome proliferator-activated receptors (PPARs), these include Wy-14.643 (Wy), which binds with great affinity to PPAR␣ and induces a strong activation of this receptor (11). 4-Phenyl butyric (4-PB) is a PP that, in contrast to other PPs, is able to induce human peroxisome proliferation (13); however, the mechanism of peroxisome proliferation remains to be elucidated. According to Liu et al. (14), 4-PB activates PPARs in astrocytes; nevertheless, they suggested that peroxisome proliferation may be independent of PPAR␣ activation.Alzheimer disease (AD) is characterized by a progressive neurodegeneration associated with extracellular deposits of amyloid ␤-peptide (A␤) in the form of senile plaques (15,16). A␤ peptide acquires neurotoxic properties when it forms homo-oligomeric species (17) or heterooligomeric species with molecules associated with mature ...

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“…Amyloidosis is thought to play a key pathogenic role in IBM; the amyloid precursor protein (APP) is proteolytically cleaved forming amyloid-β peptide (Aβ) [135], which form amyloid aggregates in patient muscle cells and may contribute to degeneration of muscle [136]. Several forms of Aβ exist, yet Aβ and Aβ [138]. APP has been implicated in a number of processes, including synpatogenesis, cellular adhesion and axon growth [139].…”

Section: Inclusion Body Myositismentioning

confidence: 99%

C. elegans models of neuromuscular diseases expedite translational research

Sleigh

Sattelle²

2010

Translational Neuroscience

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The nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

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Structure and function of amyloid in Alzheimer's disease

Cited by 124 publications

References 291 publications

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Peroxisomal Proliferation Protects from β-Amyloid Neurodegeneration

C. elegans models of neuromuscular diseases expedite translational research

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