Tau immunotherapy for Alzheimer's disease

Pedersen, Jan T.; Sigurdsson, Einar M.

doi:10.1016/j.molmed.2015.03.003

Cited by 226 publications

(183 citation statements)

References 91 publications

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“…In transgenic mouse models, passive transfer of tau-specific antibodies can reduce tau pathology (20,(33)(34)(35). Similar approaches in humans are being widely studied as potential treatments for neurodegeneration (36). However, the mechanisms by which antibodies exert their activity is unclear.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

McEwan

Falcon

Vaysburd

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

142

157

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Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubuleassociated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.T he cell's ability to identify intracellular viruses and bacteria relies on the detection of pathogen-associated molecular patterns (PAMPs) by specialized host receptors. Although highly effective at detecting microbial pathogens, this strategy is poorly equipped to identify host-derived pathogenic species such as aggregated proteins. As an alternative to PAMP detection, recent work has demonstrated that mammalian cells can use hostderived serum proteins, which are normally excluded from the cell interior, to target invading viruses and bacteria in the cytosol. For instance, nonenveloped viruses and bacteria carry antibodies with them into the cytoplasm during infection. These translocated antibodies are then sensed by the cytoplasmically expressed antibody receptor TRIM21 (tripartite motif protein 21), which binds with subnanomolar affinity to the antibody Fc domain (1-4). After binding to antibody, TRIM21 triggers a potent neutralization response that inhibits viral infection. Neutralization of infection is accompanied by degradation of viral components, which requires the activity of the proteasome and the molecular unfoldase, valosincontaining protein (VCP) or p97 (1, 5). Detection of viruses and bacteria by TRIM21 does not rely on microbial PAMPs, as model substrates such as antibody-coated latex beads can be bound and detected by TRIM21 (1, 3). We therefore hypothesized that the intracellular innate immune system could be repurposed to recognize and degrade host-derived pathogenic proteins.Microtubule-associated protein tau occurs in an assembled and hyperphosphorylated state in the cytoplasm of neurons and glial cells in Alzheimer's disease (AD), progressive supranuclear palsy, chronic traumatic encep...

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Section: Discussionmentioning

confidence: 99%

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

McEwan

Falcon

Vaysburd

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

142

157

View full text Add to dashboard Cite

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“…Although, our results suggest that CSF tau oligomers could be used as a potential biomarker in combination with the core biomarkers, additional studies, especially longitudinal ones, are required. Such studies are critical not only to diagnose the disease pathology more accurately, but also to prepare for evaluating the upcoming and exciting anti tau therapeutic approaches which have been initiated recently in clinical trials 42. Identifying novel CSF biomarkers for AD may supplement the traditional neuropsychological and imaging diagnostic techniques used for early diagnosis, and may become a useful surrogate for evaluating the pharmacological action of therapies targeting AD and other tau‐associated dementias.…”

Section: Discussionmentioning

confidence: 99%

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Sengupta

Portelius

Hansson

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWith an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD.MethodsA multicentric collaborative study involving a double‐blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls.ResultsUsing a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age‐matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls.ConclusionThese assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD.

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“…In parallel, suppression of the neurodegenerative action of APN is required. Inhibition of tau aggregation may be an efficient strategy to inhibit sequestration of APN by tau, and a clinical study of tau immunization for progressive supranuclear palsy is ongoing 68. However, stimulating endogenous production of APN using compounds such as PPAR‐ γ agonists,69 acetylcholinesterase inhibitors,70 and vitamin E71 may be detrimental in terms of the toxic gain of function of APN.…”

Section: Apn As a Novel Target For Therapies For Admentioning

confidence: 99%

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

Waragai

Ho²,

Takamatsu

et al. 2017

Ann Clin Transl Neurol

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A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both ‘gain of function’ and ‘loss of function’ of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.

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Tau immunotherapy for Alzheimer's disease

Cited by 226 publications

References 91 publications

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

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