Alzheimer's disease (AD) is an incurable neurodegenerative disease that will continue to grow as a global health challenge as societies age worldwide, yet we entirely lack therapies capable of slowing or reversing disease progression. Hyperphosphorylated Tau (pTau) tangles are pathological hallmarks of AD and, unlike ?- Amyloid, highly correlate with clinical cognitive deterioration. Microglia dominate the myeloid compartment within the central nervous system (CNS), but have a limited capacity to clear pTau that declines as AD progresses. Concomitant secretion of neurotoxic proinflammatory cytokines by these cells in response to pTau uptake hastens neurodegeneration and accelerates disease progression. At present, no therapies exist which can meaningfully diminish the highly toxic pTau species, oligomeric pTau (opTau), without triggering this deleterious neuroinflammation. Thus, there is an unmet need for a novel therapeutic that catalyzes opTau degradation without triggering inflammatory cytokine release from CNS myeloid cells. In tumor immunity, we have observed that the scavenger receptor, Fc?RIIb, is an inhibitory receptor expressed by the myeloid stroma that internalizes via clathrin-mediated endocytosis and can act to dampen cytotoxicity against diverse tumors. We propose the novel concept that the anti-inflammatory properties of scavenger receptors can be harnessed to alter the myeloid response to opTau in AD. In contrast to microglia, peripheral monocytes retain the ability to clear pTau assemblies, but do secrete neurotoxic proinflammatory cytokines. We hypothesize that monocytes engineered to bind and internalize opTau via antibody-redirected chimeric scavenger receptors (CSR) will halt the progression of AD by protecting neurons from opTau-mediated neurotoxicity while dampening inflammatory cytokine release. We have successfully engineered a peripheral macrophage/monocyte cell line to express our designed CSR construct which consists of an Fc?RIIb scaffold and an opTau single-chain variable fragment (ScFv) based on an anti-opTau antibody which limits neurodegeneration in AD mouse models. First, we will measure uptake of opTau by a monocyte/macrophage cell line expressing the FcyRIIb CSR, and determine whether internalization relies on phagocytosis or clathrin-mediated endocytosis. Next, we will investigate the efficiency of degradation of opTau by these CSR expressing cells, as well as determine whether this degradation is lysosome-dependent. To ascertain whether CSR monocytes are capable of protecting primary neurons from opTau toxicity and from their own inflammatory burst, we will co-culture primary neurons with opTau alone, with parental monocytes, or with CSR expressing monocytes and measure dendrite integrity versus fragmentation. Finally, we will perform intra-cerebroventricular infusion of CSR monocytes into Tau p301S transgenic mice starting at 6 months of age and assess their capacity to prevent or delay onset of both cognitive decline, CNS neurodegeneration, and pathologic CNS inflammation. Although high risk, our preliminary data suggests this approach has potential to protect neurons from opTau toxicity.

Public Health Relevance

Neurodegeneration in Alzheimer's disease (AD) as well as ?Tauopathies? such as Frontotemporal Dementia results from the accumulation of neurotoxic tangles of oligomeric, hyper-phosphorylated Tau protein. Microglia in the central nervous system (CNS) attempt to ingest and degrade these Tau aggregates; however, in doing so they worsen neurodegeneration by exacerbating inflammation and, in the end, largely fail to effectively reduce pathologic Tau accumulation. Leveraging knowledge from tumor immunity, we propose to engineer monocytes with chimeric scavenger receptors targeted to hyper-phosphorylated Tau which will allow them to efficiently bind, internalize and degrade neurotoxic Tau species while limiting release of deleterious inflammatory mediators.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Yang, Austin Jyan-Yu
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University of Texas MD Anderson Cancer Center
United States
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