Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

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 role of amyloid β in the pathogenesis of Alzheimer's disease

2013 ◽  
Vol 66 (5) ◽  
pp. 362-366 ◽  
Author(s):  
Barnabas James Gilbert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Experimental Models ◽  
Integrated System ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Toxic Agent ◽  
Aβ Oligomer

The amyloid-β peptide (Aβ) is widely considered to be the major toxic agent in the pathogenesis of Alzheimer's disease, a condition which afflicts approximately 36 million people worldwide. Despite a plethora of studies stretching back over two decades, identifying the toxic Aβ species has proved difficult. Debate has centred on the Aβ fibril and oligomer. Despite support from numerous experimental models, important questions linger regarding the role of the Aβ oligomer in particular. It is likely a huge array of oligomers, rather than a single species, which cause toxicity. Reappraisal of the role of the Aβ fibril points towards a dynamic relationship with the Aβ oligomer within an integrated system, as supported by evidence from microglia. However, some continue to doubt the pathological role of amyloid β, instead proposing a protective role. If the field is to progress, all Aβ oligomers should be characterised, the nomenclature revised and a consistent experimental protocol defined. For this to occur, collaboration will be required between major research groups and innovative analytical tools developed. Such action must surely be taken if amyloid-based therapeutic endeavour is to progress.

scholarly journals Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Erik C. B. Johnson ◽  
Kaitlyn Ho ◽  
Gui-Qiu Yu ◽  
Melanie Das ◽  
Pascal E. Sanchez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neurodegenerative Disorder ◽  
Epileptiform Activity ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Behavioral Abnormalities ◽  
Amyloid Deposits

Abstract Background Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.

The consequences of mitochondrial amyloid β-peptide in Alzheimer's disease

2010 ◽  
Vol 426 (3) ◽  
pp. 255-270 ◽  
Author(s):  
Kirsty E. A. Muirhead ◽  
Eva Borger ◽  
Laura Aitken ◽  
Stuart J. Conway ◽  
Frank J. Gunn-Moore
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Permeability Transition ◽  
Amyloid Β Peptide ◽  
Cyclophilin D ◽  
Aβ Amyloid

The Aβ (amyloid-β peptide) has long been associated with Alzheimer's disease, originally in the form of extracellular plaques. However, in the present paper we review the growing evidence for the role of soluble intracellular Aβ in the disease progression, with particular reference to Aβ found within the mitochondria. Once inside the cell, Aβ is able to interact with a number of targets, including the mitochondrial proteins ABAD (amyloid-binding alcohol dehydrogenase) and CypD (cyclophilin D), which is a component of the mitochondrial permeability transition pore. Interference with the normal functions of these proteins results in disruption of cell homoeostasis and ultimately cell death. The present review explores the possible mechanisms by which cell death occurs, considering the evidence presented on a molecular, cellular and in vivo level.

Cathepsins S, B and L with aminopeptidases display β-secretase activity associated with the pathogenesis of Alzheimer’s disease

2011 ◽  
Vol 392 (6) ◽  
Author(s):  
Israel Schechter ◽  
Etty Ziv
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Bond Yields ◽  
Disease Modifying Drugs ◽  
Secretase Activity ◽  
Cysteine Cathepsin ◽  
Aβ Amyloid ◽  
Rapid Removal

Abstract β-site APP-cleaving enzyme (BACE1) cleaves the wild type (WT) β-site very slowly (k cat /K m: 46.6 m -1 s -1). Therefore we searched for additional β-secretases and identified three cathepsins that split the WT β-site much faster. Human cathepsin S cleaves the WT β-site (k cat /K m: 54 700 m -1 s -1) 1170-fold faster than BACE1 and cathepsins B and L are 440- and 74-fold faster than BACE1, respectively. These cathepsins split two bonds flanking the WT β-site (K-MD-A), where the K-M bond (85%) is cleaved more efficiently than the D-A bond (15%). Cleavage at the major K-M bond yields Aβ (amyloid β-peptide) extended by N-terminal Met that should be removed to generate Aβ initiated by Asp1. The activity of cytosol and microsomal aminopeptidases on relevant peptides revealed rapid removal of N-terminal Met but not N-terminal Asp. Brain aminopeptidases showed similar specificity. Thus, aminopeptidases would convert Aβ extended by Met into regular Aβ (Asp1) found in amyloid plaques. Earlier studies indicate that Aβ is likely produced in the endosome and lysosome system where cathepsins S, B and L are localized and cysteine cathepsin inhibitors reduce the level of Aβ in cells and animals. Taken together, cathepsins S, B and L deserve further evaluation as therapeutic targets to develop disease modifying drugs to treat Alzheimer’s disease.

scholarly journals Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial

2010 ◽  
Vol 38 (4) ◽  
pp. 962-966 ◽  
Author(s):  
Khalid Iqbal ◽  
Xiaochuan Wang ◽  
Julie Blanchard ◽  
Fei Liu ◽  
Cheng-Xin Gong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Neurofibrillary Degeneration ◽  
Amyloid Β Peptide ◽  
Neuronal Nucleus ◽  
Disease Modifying Drugs ◽  
Pp2a Activity ◽  
Therapeutic Opportunity ◽  
Ad Alzheimer’S Disease

Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Aβ1–42 (where Aβ is amyloid β-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of the different aetiopathogenic mechanisms involved and stratification of AD patients by different disease subgroups in clinical trials. We have identified a novel aetiopathogenic mechanism of AD which is initiated by the cleavage of SET, also known as inhibitor-2 (I2PP2A) of PP2A (protein phosphatase 2A) at Asn175 into N-terminal (I2NTF) and C-terminal (I2CTF) halves and their translocation from the neuronal nucleus to the cytoplasm. AAV1 (adeno-associated virus 1)-induced expression of I2CTF in rat brain induces inhibition of PP2A activity, abnormal hyperphosphorylation of tau, neurodegeneration and cognitive impairment in rats. Restoration of PP2A activity by inhibition of the cleavage of I2PP2A/SET offers a promising therapeutic opportunity in AD with this aetiopathogenic mechanism.

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.

Sign in / Sign up

Export Citation Format

Share Document