Arthritis and alzheimers relationship

arthritis and alzheimers relationship

Controversial data are available about the relationship between Alzheimer's disease (AD) and rheumatoid arthritis (RA). An inverse. J Alzheimers Dis. ;31(3) doi: /JAD Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a. The causal relationship between RA and AD was assessed using . Studies investigating Rheumatoid Arthritis as a Risk Factor for Alzheimer's.

These biological mechanisms enable cells to quickly respond to environmental changes. To date, several miRNAs were found to be crucial for immune cells biology Baltimore et al. Moreover, through the generation of knockout and transgenic mice for specific miRNAs, it has become clear that they can be major regulators and fine tuners of gene expression in different pathologies including AD and RA. We will describe the genetic regulation of their expression related to their single nucleotide gene polymorphisms SNPs.

IL-6 is an inflammatory mediator with dichotomic actions on the central nervous system CNSshowing neurotrophic as well as harmful properties. IL-6 expression was shown to be age-dependent since elderly people are characterized by significantly higher IL-6 gene expression compared to younger people Ershler and Keller, In AD, IL-6 was found to be overexpressed in the brain tissue particularly in the peri-plaques areas Strauss et al.

arthritis and alzheimers relationship

Controversial data are available on the IL-6 biologic effects on intellective performance. IL-6 gene deletion was found to facilitate learning and memory skills in murine models Braida et al.

Moreover no data are available on possible influences on AD features in people targeted with IL-6 blocking agents. In fact, Licastro et al.

arthritis and alzheimers relationship

In particular IL-6 polymorphism seems to be associated with IL polymorphism, an anti-inflammatory cytokine Combarros et al. Therefore the possible explanation of those conflicting data could be found in the impact of polymorphisms other than IL-6 in the developmental risk of AD.

It has been demonstrated that healthy subjects carrying the C allele are characterized by significantly higher IL-6 plasma levels compared to the G allele carriers Rivera-Chavez et al. RA patients with the C allele showed a higher risk of extra-articular clinical manifestations compared to the G allele carriers Jenny et al.

A strong inducer of IL-6 could be interleukin-1 IL IL-1 was shown to be overexpressed in AD brain mainly in activated surrounding plaques microglia cells and it seems to increase amyloid deposition and plaque formation Sardi et al. IL-1 overexpression in CNS was supposed to be an early feature of AD preceding and contributing to the plaque formation. Furthermore the presence of damaged neurons in the plaque was described to be an important trigger factor for the increase of IL-1 expression in a pathogenetic biologic loop Griffin and Mrak, It has been reported that people with T allele of IL-1 gene were characterized by significant higher risk of developing AD Grimaldi et al.

Similarly, the IL-1 gene polymorphism has been studied to identify the association with RA showing that the T allele was a susceptibility factor for RA development in Turkish patients Araman et al. Interestingly, the presence of the G allele was associated with a significantly better therapeutic response in RA patients Zeng et al.

Finally interleukin ILa major anti-inflammatory cytokine, is synthesized in CNS where it seems to limit inflammation in several pathological conditions like strokemultiple sclerosismeningitis, and AD, promoting survival of neurons and all glial cells Strle et al. The percentage of A carrier subjects was significantly increased among AD patients. Recently Zhang et al. Interestingly, allelic polymorphisms in the IL gene promoter may contribute to the regulation of autoantibodies production in RA.

In animals, miRNAs are involved in the regulation of multiple biological pathways by post-transcriptionally repressing the expression of protein-encoding genes. Nearly half of the known human miRNAs are found in clusters functionally related to their target genes involved in the same cellular pathway.

Because of the crucial role played by miRNAs in gene expression regulation, the discovery of a potential link between miRNAs and the pathophysiology of AD and RA has stimulated research towards obtaining a more integrated view in the deregulated cellular networks in RA and maybe accessing a key pivotal pathogenetic mediator. Recent studies indicate that miRa plays a pivotal role in the pathogenesis of RA.

Particularly, in situ hybridization demonstrated miRa expression in cells located in the lining and sublining layer in synovial tissue of RA patients. Despite its effect on the inflammatory cascade, miRa was shown to have an important role in the inhibition of bone destruction in the murine model of collagen-induced arthritis. TRAF6 is an important mediator in osteoclastogenesis and its downregulation after miRa overexpression can explain this biologic link Pauley et al.

Overall the data at hand show that miRa overexpression characterizes myeloid cells in RA and contributes to the inflammatory cascade while the administration of miRa reduces the erosive process acting on the osteoclastogenetic pathway, thus allowing to decouple inflammation and bone destruction.

To date, few data are available on the role of this single nucleotide polymorphism distribution showing that the genotypes of miRa rs were not related to the risk of RA development in Chinese and Mexican populations Yang et al. AD patients are characterized by a deregulation in miRNA networks among whom miRa is involved in neuroinflammatory process as well as in the AAP metabolism. Recent findings indicate that miRa plays an important role in the two major pathogenetic phenomena of AD, neuroinflammation, and APP metabolism deregulation.

However, the exact biological mechanism of this system has still to be clarified. Another molecular mechanism showing the role of miRa in neuroinflammation can be explained by the studies conducted on another mRNA target of miRa, the complement factor H CFH.

The growing link between inflammation and cancer, heart disease and Alzheimer's - The Listener

CFH plays an important role in neuroinflammation being an inhibitory factor of the immune and inflammatory responses in the brain Lukiw et al. AD hippocampus tissue showed a significant reduction in CFH protein. Based on these findings, miRa arose as an important epigenetic regulator of the inflammatory response in AD and RA. However, the final effect of miRa deregulation in the inflammatory cascade seems to be dependent on the cell type as well as on the different target mRNAs.

Conclusions Controversial data about the incidence rate of AD in RA patients are available in the scientific literature and so far several factors important in the pathogenesis of both diseases have been studied. The deregulation of multiple genetic and epigenetic mediators involved in the inflammatory cascade is a common feature in AD and RA. The balance between the IL-6 driven and the miRa pathway is likely to play a critical role in controlling the incidence of AD in treated RA patients.

Of interest will be the results in RA patients receiving anti-IL-6 biological therapies in the near future.

arthritis and alzheimers relationship

Key Points - Rheumatoid arthritis RA is a chronic systemic inflammatory disease, primarily of the joints, characterized by inflammatory changes in the synovial membranes and articular structures leading to damage of the bony structures. The condition primarily occurs after age 60 and is pathologically characterized by severe cortical brain atrophy. IL-1 is a pro-inflammatory soluble factor produced by monocytes-macrophages and other cells, which activates T-lymphocytes and potentiates their response to mitogens or antigens.

It represents one of the key molecules in the maintenance of chronic inflammation in rheumatoid arthritis. IL is an anti-inflammatory cytokine produced by a variety of cell types including T-cells, monocytes, dendritic cells, and epithelial cells that exerts several effects on immunoregulation and inflammation.

To date, controversial data about the incidence rate of AD in RA patients are available and so far, several factors important in the pathogenesis of both diseases have been studied. The deregulation of multiple genetic and epigenetic mediators involved in the inflammatory cascade is a common feature in RA and AD.

Disclosure The authors report no conflicts of interest. Corresponding Author Gianfranco Ferraccioli, M.

Rheumatoid Arthritis and Alzheimer Disease: Possible Cellular and Molecular Links

Interleukin-1 receptor antagonist IL-1RN and interleukin-1B gene polymorphisms in Turkish patients with rheumatoid arthritis. Clin Exp Rheum 24 6: Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci Impaired hippocampus-dependent and -independent learning in IL-6 deficient mice.

Behav Brain Res 1: Nat Immunol 9 8: J Alzheimers Dis 28 4: Novel regulatory mechanisms in inflammatory arthritis: Immunol Cell Biol 90 3: Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest 6: GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimers Dis 21 2: Cognitive function in young and adult IL interleukin -6 deficient mice.

arthritis and alzheimers relationship

Behav Brain Res 2: Alzheimers Dement 7 4: Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: Joint Bone Spine 77 5: J Neurol 4: J Neuroinflammation 23 6: J Biol Chem J Neurol 3: Brain Res Rev 61 2: J Alzheimer Dis 23 2: Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty.

Annu Rev Med IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur J Neurosci 7 Mol Med 16 Rheumatoid arthritis and Alzheimer disease: J Gerontol Geriatric Res 1: J Neurol 7: Interleukin-6 IL-6 a molecule with both beneficial and destructive potentials. Prog Neurobiol 52 5: Role of genes and environments for explaining Alzheimer disease. To date, many epidemiological studies have been performed suggesting controversial data about the prolonged use of NSAIDs and their possible protective effect, reducing AD risk.

Moreover, Stricker et al. This finding was confirmed through a systematic review of prospective and non-prospective studies published from to that concluded that NSAIDs exposure was associated with decreased risk of AD disease [ 18 ].

Nevertheless, except for a small-size 6-months clinical trial reporting the positive effect of indomethacin on individuals with mild to moderate AD [ 20 ], many clinical trials demonstrated no benefits of NSAIDs on cognitive performance in symptomatic AD patients. A multicenter, randomized, double—blind, controlled trial on mildto- moderate AD patients randomized to receive naproxen, rofecoxib or placebo did not show any significant beneficial effect of NSAIDs on AD progression [ 21 ].

Similar results derived from a randomized controlled trial using indomethacin versus placebo in 51 mild-to-moderate AD patients [ 22 ]. Thus the anti-inflammatory approach is really effective eventually only in primary prevention of AD, not in treatment of AD. Taking into account that different NSAIDs have different capacity in crossing the brain -blood-barrier because of their lipophilicity, part of the beneficial effects of NSAIDs on reducing the risk and delaying the onset of AD may be explained by their common anti-inflammatory effect through COX enzymes inhibition.

It has been proposed that COX-1 should be a preferential target being up-regulated in microglia [ 24 ] probably COX-2 plays a minor role being involved only at the later stage of AD animal models [ 25 ].

New insights are emerging about a direct anti-amyloidogenic effect of NSAIDs in vitro and in animal models. CsA also seems to prevent APP overexpression and amyloidogenic peptides overproduction [ 33 ] but conversely it has been described to enhance Tau phosphorylation. Phosphatase calcineurin, that is a specific target for CsA, is known to be upregulated in AD models inducing astrogliosis and neuroinflammation [ 34 ].

Few evidences are available on Methotrexate MTX: There are no data about the effects of Leflunomide on AD.

Treating Alzheimer's with Turmeric

It increases production of the precursor necessary for amyloid plaques and neurifibrillary tangles formation [ 37 ] and affects synaptic physiology acting as a gliotransmitter [ 3839 ]. Based on these findings, it is fair to suppose a possible tight intrinsic link in RA pathogenesis able to explain itself the protective effect of RA against AD.