RESUMO
Toxic amyloid beta (Aß) species cause synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aß production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aß and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aß production and memory impairment under hypoxia.
Assuntos
Doença de Alzheimer/enzimologia , Comportamento Animal , Encéfalo/enzimologia , Endopeptidases/metabolismo , Proteínas de Membrana/metabolismo , Memória , Piruvato Quinase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/fisiopatologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Bases de Dados Genéticas , Modelos Animais de Doenças , Endopeptidases/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Piruvato Quinase/genética , Reconhecimento Psicológico , Transdução de Sinais , Memória Espacial , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Transcrição Gênica , Proteínas de Ligação a Hormônio da TireoideRESUMO
The enzyme γ-secretase generates ß-amyloid (Aß) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase-regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aß generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aß production. Moreover, SERP1 abundance, γ-secretase assembly, and Aß production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aß production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of γ-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD.
