Acetylsalicylic acid decreases tau phosphorylation at serine 422

doi:10.1016/j.neulet.2005.11.066

Neuroscience Letters

Volume 396, Issue 1, 20 March 2006, Pages 77-80

https://doi.org/10.1016/j.neulet.2005.11.066 Get rights and content

Abstract

Tau protein pathology in Alzheimer's disease is characterized by the hyperphosphorylation of tau at some specific sites. One of these sites is serine 422 which modification has been correlated with a possible toxic effect of phosphotau in neural cells. In this work, we have found that in the presence of acetylsalicylic acid, at a concentration like that used for anti-inflammatory treatments, tau phosphorylation at serine 422 decreases.

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Acknowledgements

We thank to Dr. J.J. Lucas for critical reading of the manuscript. This work was supported by Spanish Ministry of Education, Fundación “Severo Ochoa” and Science (CICYT) grants.

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Several clinical trials aiming to verify the possibility that acetylsalicylic acid halts the progress of AD have been conducted. One of them found that this well-known NSAID may decrease hyperphosphorylation of tau proteins (Tortosa et al., 2006). According to another piece of research aspirin, as opposed to other checked NSAIDs, did not reduce the risk of AD and dementia (Szekely et al., 2008).
Aspirin (acetylsalicylic acid), the oldest synthetic drug, was originally used as an anti-inflammatory medication. Being an irreversible inhibitor of COX (prostaglandin-endoperoxide synthase) enzymes that produce precursors for prostaglandins and thromboxanes, it has gradually found several other applications. Sometimes these applications are unrelated to its original purpose for example its use as an anticoagulant. Applications such as these have opened opportunities for new treatments. In this case, it has been tested in patients with cardiovascular disease to reduce the risk of myocardial infarct. Its function as an anticoagulant has also been explored in the prophylaxis and treatment of pre-eclampsia, where due to its anti-inflammatory properties, aspirin intake may be used to reduce the risk of colorectal cancer. It is important to always consider both the risks and benefits of aspirin's application. This is especially important for proposed use in the prevention and treatment of neurologic ailments like Alzheimer's disease, or in the prophylaxis of myocardial infarct. In such cases, the decision if aspirin should be applied, and at what dose may be guided by specific molecular markers. In this revived paper, the pleiotropic application of aspirin is summarized.
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One of the neuropathological hallmarks of AD is the amyloid plaque, and aspirin might prevent or reverse formation of amyloid-β fibrils.13,14 Aspirin also decreases tau phosphorylation at serine 422, which might be an important event in the aggregation of amyloid-β peptide.15 Furthermore, aspirin can suppress the secretion of amyloid precursor protein from human platelets,16 and at higher doses attenuates inflammatory processes through inhibition of cyclo-oxygenases, which might also be important in AD.17
Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD.
310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233.
Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0·10 points higher (95% CI −0·37 to 0·57; p=0·7) and mean BADLS score was 0·62 points lower (−1·37 to 0·13; p=0·11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4·4, 95% CI 1·5–12·8; p=0·007); three (2%) patients in the aspirin group had fatal cerebral bleeds.
Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.
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Citation Excerpt :
Regarding this issue, studies performed in our laboratory have demonstrated that proinflammatory cytokines modulate the activity of cdk5 (7), a key enzyme in the anomalous phosphorylation of tau. Interestingly, it has recently been demonstrated that acetylsalicylic acid, a non-selective COX inhibitor, decreases tau phosphorylation at serine 422 (134), a posttranscriptional modification relevant to AD pathogenesis. A subset of NSAIDs has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-peptide Aβ (1–42).
During the past few years, an increasing set of evidence has supported the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration. Neurons and glial cells, together with brain vessels, constitute an integrated system for brain function. Inflammation is a process related with the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Several hypotheses have been postulated to explain the pathogenesis of AD, but none provides insight into the early events that trigger metabolic and cellular alterations in neuronal degeneration. The amyloid hypothesis was sustained on the basis that Aβ-peptide deposition into senile plaques is responsible for neurodegeneration. However, recent findings point to Aβ oligomers as responsible for synaptic impairment in neuronal degeneration. Amyloid is only one among many other major factors affecting the quality of neuronal cells. Another explanation derives from the tau hypothesis, supported by the observations that tau hyperphosphorylations constitute a common feature of most of the altered signaling pathways in degenerating neurons. Altered tau patterns have been detected in the cerebrospinal fluids of AD patients, and a close correlation was observed between the levels of hyperphosphorylated tau isoforms and the degree of cognitive impairment. On the other hand, the anomalous effects of cytokines and trophic factors share in common the activation of tau hyperphosphorylation patterns. In this context, a neuroimmunological approach to AD becomes relevant. When glial cells that normally provide neurotrophic factors essential for neurogenesis are activated by a set of stressing events, they overproduce cytokines and NGF, thus triggering altered signaling patterns in the etiopathogenesis of AD. A solid set of discoveries has strengthened the idea that altered patterns in the glia-neuron interactions constitute early molecular events within the cascade of cellular signals that lead to neurodegeneration in AD. A direct correlation has been established between the Aβ-induced neurodegeneration and cytokine production and its subsequent release. In effect, neuroinflammation is responsible for an abnormal secretion of proinflammatory cytokines that trigger signaling pathways that activate brain tau hyperphosphorylation in residues that are not modified under normal physiological conditions. Other cytokines such as IL-3 and TNF-α seem to display neuroprotective activities. Elucidation of the events that control the transitions from neuroprotection to neurodegeneration should be a critical point toward elucidation of AD pathogenesis.
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Acetylsalicylic acid decreases tau phosphorylation at serine 422

Abstract

Section snippets

Acknowledgements

J. Biol. Chem.

FEBS Lett.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

FEBS Lett.

Role of tau protein in both physiological and pathological conditions

Physiol. Rev.

Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones

Cancer Res.