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1.
Biochem Biophys Res Commun ; 524(3): 764-771, 2020 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-32037089

RESUMEN

ß-Amyloid (Aß) plaque in the brains of patients with Alzheimer's disease (AD) is mainly caused by impaired clearance of Aß by glial cells, including microglia and astrocytes. Because microglia play an important protective role in the central nervous system, many efforts have been made to identify agents that effectively improve microglial Aß phagocytosis. This study found that TLQP-21, which is cleaved from VGF (VGF nerve growth factor inducible) precursor protein, enhanced Aß phagocytosis and degradation by microglial BV2 cells. TLQP-21 also improved microglial phagocytic activity and promoted fibrillar amyloid-ß (fAß) uptake by microglial BV2 cells via a C3AR1-dependent mechanism. Moreover, TLQP-21 stimulated Aß degradation by enhancing lysosome activity, thereby enhancing fAß clearance. These results suggest that treatment with TLQP-21 may be a novel therapeutic strategy to efficiently enhance microglial Aß clearance in AD.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Espacio Extracelular/metabolismo , Microglía/metabolismo , Fragmentos de Péptidos/farmacología , Amiloide/efectos de los fármacos , Animales , Línea Celular , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Microglía/efectos de los fármacos , Neuropéptidos/farmacología , Fagocitosis/efectos de los fármacos , Proteolisis/efectos de los fármacos , Receptores de Complemento/metabolismo
2.
J Clin Invest ; 133(8)2023 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-36917188

RESUMEN

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Tauopatías , Ratones , Animales , Anticuerpos Monoclonales/farmacología , Proteínas tau/genética , Proteínas tau/metabolismo , Lisina , Tauopatías/tratamiento farmacológico , Modelos Animales de Enfermedad , Encéfalo/metabolismo
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