RESUMO
Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.
Assuntos
Doença de Alzheimer , Peptídeos , Proteína Fosfatase 2 , Tauopatias , Proteínas tau , Animais , Humanos , Camundongos , Ratos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Camundongos Transgênicos , Microtúbulos/efeitos dos fármacos , Microtúbulos/genética , Terapia de Alvo Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/genética , Proteínas tau/genética , Tauopatias/tratamento farmacológico , Tauopatias/genética , Tauopatias/patologiaRESUMO
Bisphosphonates can directly inhibit osteoclasts, which may lead to increased bone density, reduced blood flow, and osteonecrosis of the jaw. Bisphosphonate-related osteonecrosis is usually observed in the jaw bone. In this article, we report a patient with bisphosphonate-related osteonecrosis of the jaw (BRONJ) complicated with wrist scaphoid osteomyelitis. Furthermore, we introduce the pathogenesis, treatment, and prevention of BRONJ.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Osteomielite , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/complicações , Difosfonatos , Humanos , Osteomielite/complicações , Punho/patologiaRESUMO
Cleidocranial dysplasia (CCD) is a rare hereditary disorder characterized by skeletal malformations and dental abnormalities. Mutations of the transcription factor RUNX2 are responsible for the pathogenesis of CCD. We present a case of a 10-year-old boy with CCD, presenting with hypoplastic clavicles, delayed closure of the fontanelles, retarded exfoliation of the deciduous teeth, retarded eruption of the permanent teeth, and multiple impacted supernumerary teeth. Based on the clinical and radiographic examination results showing abnormalities of the bones and teeth, a diagnosis was reached easily, but it was difficult to achieve a complete curative effect. We carried out a highly organized schedule of treatment, including extraction of the deciduous and supernumerary teeth, partial resection of alveolar bone, distraction of impacted teeth, and orthodontic surgery. After 7-year follow-up, the patient has achieved acceptable occlusion and midfacial appearance. The main objectives of this study were to present the diagnosis and treatment of CCD and to emphasize the benefits of combined orthodontic-surgical sequential treatment.
