Pathways linking Aβ and tau pathologies

2010 ◽  
Vol 38 (4) ◽  
pp. 993-995 ◽  
Author(s):  
Frank M. LaFerla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Convincing Evidence ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Amyloid ◽  
Cellular Compartments

Aβ (amyloid β-peptide) and tau are the main proteins that misfold and accumulate in amyloid plaques and NFTs (neurofibrillary tangles) of Alzheimer's disease and other neurological disorders. Historically, because plaques and NFTs accumulate in diverse cellular compartments, i.e. mainly extracellularly for plaques and intracellularly for NFTs, it was long presumed that the constituent proteins formed these lesions via unrelated pathways. Animal and cell studies over the last decade, however, have provided convincing evidence to show that Aβ can facilitate the development of tau pathology by altering several cell-dependent and -independent mechanisms. In the present article, results are reviewed from several laboratories that show that modulating Aβ pathology can directly affect the development of tau pathology, which has significant implications for the treatment of Alzheimer's disease.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

scholarly journals Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 359-373 ◽  
Author(s):  
Christopher D Morrone ◽  
Paolo Bazzigaluppi ◽  
Tina L Beckett ◽  
Mary E Hill ◽  
Margaret M Koletar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Function ◽  
Spatial Memory ◽  
Regional Differences ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Barnes Maze ◽  
Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction

2007 ◽  
Vol 35 (5) ◽  
pp. 1219-1223 ◽  
Author(s):  
M.J. Rowan ◽  
I. Klyubin ◽  
Q. Wang ◽  
N.W. Hu ◽  
R. Anwyl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Nitrosative Stress ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Aβ Amyloid

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Aβ (amyloid β-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Aβ oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Aβ, the αv integrin extracellular cell matrix-binding protein and the cytokine TNFα (tumour necrosis factor α) type-1 death receptor mediate Aβ oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFα or genetic knockout of TNF-R1s (type-1 TNFα receptors) prevented Aβ-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to αv-containing integrins abrogated LTP block by Aβ. Protection against the synaptic plasticity-disruptive effects of soluble Aβ was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Aβ oligomers in preclinical AD.

The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer's disease brain

2007 ◽  
Vol 35 (3) ◽  
pp. 574-576 ◽  
Author(s):  
J.H. Stockley ◽  
C. O'Neill
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Protein Levels ◽  
Rate Limiting Step ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease ◽  
And Function

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing changes in β-secretase enzyme kinetics in AD brain caused by an increased Vmax. This article gives a brief review of studies which have examined BACE1 protein levels and β-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.

scholarly journals Mitochondrial β-amyloid in Alzheimer's disease

2011 ◽  
Vol 39 (4) ◽  
pp. 868-873 ◽  
Author(s):  
Eva Borger ◽  
Laura Aitken ◽  
Kirsty E.A. Muirhead ◽  
Zoe E. Allen ◽  
James A. Ainge ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Transgenic Animals ◽  
Transgenic Animal ◽  
Major Effect ◽  
Amyloid Β Peptide ◽  
Toxic Response ◽  
Intracellular Location ◽  
Aβ Amyloid

It is well established that the intracellular accumulation of Aβ (amyloid β-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aβ can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aβ, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aβ accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aβ; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD–Aβ interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.

Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

2007 ◽  
Vol 35 (5) ◽  
pp. 974-979 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Interactions ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

Intracellular copper deficiency increases amyloid-β secretion by diverse mechanisms

2008 ◽  
Vol 412 (1) ◽  
pp. 141-152 ◽  
Author(s):  
Michael A. Cater ◽  
Kelly T. McInnes ◽  
Qiao-Xin Li ◽  
Irene Volitakis ◽  
Sharon La Fontaine ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Copper Deficiency ◽  
Human Fibroblasts ◽  
Amyloid Β ◽  
Copper Accumulation ◽  
Amyloid Β Peptide ◽  
Human Neuroblastoma ◽  
Aβ Amyloid ◽  
Intracellular Copper

In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Aβ (amyloid β-peptide) production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Aβ. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)α into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPβ and produced more amyloidogenic β-cleaved APP C-termini (C99). The level of Aβ secreted from copper-deficient fibroblasts was however regulated and limited by α-secretase cleavage. APP can be processed by both α- and β-secretase, as copper-deficient fibroblasts secreted sAPPβ exclusively, but produced primarily α-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Aβ secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Aβ secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzheimer's disease.

Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties

2017 ◽  
Vol 13 (8) ◽  
pp. 1545-1551 ◽  
Author(s):  
Elaheh Jamasbi ◽  
Frances Separovic ◽  
Mohammed Akhter Hossain ◽  
Giuseppe Donato Ciccotosto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Amyloid Aggregation ◽  
Cell Binding ◽  
The Brain

Phosphorylation of Aβ42 promotes the formation of amyloid plaques in the brain, which lack the neurotoxic properties associated with oligomeric species causing pathogenesis in Alzheimer's disease.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

scholarly journals Ameliorative effects of olibanum essential oil on learning and memory in Aβ1-42-induced Alzheimer’s disease mouse model

2020 ◽  
Vol 19 (8) ◽  
pp. 1643-1651
Author(s):  
Zhenzhen Zhang ◽  
Wenhua Chen ◽  
Jie Luan ◽  
Dagui Chen ◽  
Lina Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Essential Oil ◽  
Learning And Memory ◽  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Morris Water Maze Test ◽  
Amyloid Β Peptide ◽  
Brain Tissues

Purpose: To study the effect of olibanum essential oil (OEO) on learning and memory in Alzheimer’s disease (AD) mouse.Methods: Mice were administered the 42-amino acid form of amyloid β-peptide (Aβ1-42) to induce AD and then treated with OEO at 150, 300, and 600 mg/kg, p.o. for two weeks. Following treatment, the AD mice were assessed by step-down test (SDT), dark avoidance test (DAT), and Morris water maze test (MWM). Blood and brain tissues were collected for biochemical assessments. Gas chromatographymass spectroscopy was used to analyze the main constituents of OEO.Results: The main constituents of OEO were limonene, α-pinene, and 4-terpineol. Treatment with OEO prolonged t latency in SDT and DAT, but decreased error times. Escape latency decreased and crossing times were rose in the MWM following OEO treatment (p < 0.5). Treatment with OEO also enhanced the acetylcholine levels and decreased the acetylcholinesterase levels in serum and brain tissue (p < 0.5). Additionally, OEO reduced amyloid plaques in the hippocampus and protected hippocampal neurons from damage. Furthermore, OEO decreased c-fos expression in  hippocampus tissues from AD mice (p < 0.5).Conclusion: OEO has significant ameliorative effect AD-induced deterioration in learning and memory in AD mouse induced by Aβ1-42. The mechanisms of these effects are related to increased acetylcholine contents, reduction of amyloid plaques, protection of hippocampal neurons, and downregulation of c-fos in brain tissues. The results justify the need for further investigation of candidate drugs derived from OEO for the  management of AD. Keywords: Olibanum, Essential oil, Learning, Memory, AD

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