New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.

Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in the context of the earlier small molecules described as "γ-secretase modulators" (GSM). We review here the structure, function, and pathobiology of γ-secretases, with a focus on how mutations in presenilin genes result in early-onset AD. Significant progress has been made in generating compounds that act in a manner opposite to pathogenic presenilin mutations: they stabilize the proteinase-substrate complex, thereby increasing the processivity of substrate cleavage and altering the size spectrum of Aß peptides produced. We propose the term "γ-secretase allosteric stabilizers" (GSAS) to distinguish these compounds from the rather heterogenous class of GSM. The GSAS represent, in theory, a precision medicine approach to the prevention of amyloid deposition, as they specifically target a discrete aspect in a complex cell biological signalling mechanism that initiates the pathological processes leading to Alzheimer's disease.

Lipid environment modulates processivity and kinetics of a presenilin homolog acting on multiple substrates in vitro.

Intramembrane proteases (IPs) hydrolyze peptides in the lipid membrane. IPs participate in a number of cellular pathways including immune response and surveillance, and cholesterol biosynthesis, and they are exploited by viruses for replication. Despite their broad importance across biology, how activity is regulated in the cell to control protein maturation and release of specific bioactive peptides at the right place and right time remains largely unanswered, particularly for the intramembrane aspartyl protease (IAP) subtype. At a molecular biochemical level, different IAP homologs can cleave non-biological substrates, and there is no sequence recognition motif among the nearly 150 substrates identified for just one IAP, presenilin-1, the catalytic component of γ-secretase known for its involvement in the production of amyloid-ß plaques associated with Alzheimer disease. Here we used gel-based assays combined with quantitative mass spectrometry and FRET-based kinetics assays to probe the cleavage profile of the presenilin homolog from the methanogen Methanoculleus marisnigri JR1 as a function of the surrounding lipid-mimicking environment, either detergent micelles or bicelles. We selected four biological IAP substrates that have not undergone extensive cleavage profiling previously, namely, the viral core protein of Hepatitis C virus, the viral core protein of Classical Swine Fever virus, the transmembrane segment of Notch-1, and the tyrosine receptor kinase ErbB4. Our study demonstrates a proclivity toward cleavage of substrates at positions of low average hydrophobicity and a consistent role for the lipid environment in modulating kinetic properties.

Influência genética sobre a doença de Alzheimer de início precoce / Genetic influence on early onset Alzeimer's disease

CONTEXTO: A doença de Alzheimer de início precoce (DAIP) representa 5 por cento de todos os casos de doença de Alzheimer e está relacionada a mutações gênicas. OBJETIVO: Apresentar a influência de mutações gênicas na DAIP. MÉTODOS: Revisão da literatura, a partir de 1992, empregando o banco de dados PubMed. RESULTADOS: O alelo E*4 do gene da apolipoproteína E interfere na DAIP. No gene da proteína precursora da amiloide, foram descritas 20 mutações, que causam cerca de 10 por cento a 15 por cento dos casos de DAIP. Mutações no gene das presenilinas 1 e 2 causam 30 por cento a 70 por cento dos casos de DAIP. No gene da PSN1, há 30 mutações de troca de aminoácidos e três inserções/deleções. O gene da PSEN2 apresenta seis mutações de troca de aminácidos. No gene MAPT, apenas uma mutação se relaciona exclusivamente com a DA. CONCLUSÕES: O uso de informações genéticas para a detecção precoce de possíveis pacientes com DAIP ainda é bastante limitado. A heterogeneidade genética é ampla. Algumas mutações descritas nesta revisão foram responsáveis pela doença de Alzheimer em apenas algumas poucas famílias. A aplicação clínica desses métodos no rastreamento de indivíduos em risco para a DAIP ainda exige cautela.

BACKGROUND: Early onset Alzheimer's disease (EOAD) represents 5 percent of all cases of Alzheimer's disease, and it is connected to genic mutations. OBJECTIVES: To present the influence of genic mutations in EOAD. METHODS: Review of current literature, starting from 1992, utilizing the PubMed data bank. RESULTS: The E*4 allele of the apolipoprotein E gene interferes in EOAD. In the gene of the Amyloid Precursor Protein, 20 mutations were described, causing 10 percent to 15 percent of the cases of EOAD. Mutations in the gene of presenilins 1 and 2 cause 30 percent to 70 percent of the cases of EOAD. In PSN1 gene, 30 aminoacid change mutations and 3 insertions/deletions are known. In the PSEN2 gene, there are 6 aminoacid change mutations. Only one mutation in the MAPT gene is selectively associated with Alzheimer's disease. CONCLUSIONS: The use of genetic information for early detection of possible pacients of EOAD is still very limited. Genetic heterogeneity is broad. Some mutations described in this review were responsible for Alzheimer's disease only in a few families. The clinical utilization of these methods for screening individuals at risk for EOAD still asks for caution.

Genética en la enfermedad de Alzheimer / Genetics of Alzheimer’s disease

Introducción y desarrollo. La enfermedad de Alzheimer (EA), la causa más frecuente de demencia, es una enfermedad compleja en la que factores ambientales y genéticos interactúan para dar lugar al fenotipo final. Existen tres genes que se han asociado a formas preseniles autosómicas dominantes de la enfermedad: el gen que codifica para la proteína precursora del péptido beta-amiloide (APP) y los genes de las presenilinas (PSEN1 y PSEN2). Un cuarto gen, el gen de la apolipoproteína E (APOE), es el único gen mayor de susceptibilidad para las formas, tanto esporádicas como familiares, tardías, de EA. Aunque se han realizado miles de estudios genéticos, se conoce poco sobre la arquitectura genética de la EA. Aun así, en los últimos tres años ha habido un salto cualitativo extraordinario gracias a la utilización de las novedosas tecnologías de genotipado masivo, las cuales han permitido un análisis exhaustivo del genoma. Conclusión. Esta revisión resume el conocimiento actual de las causas genéticas relacionadas con la EA (AU)

Introduction and development. Alzheimer’s disease (AD), the leading cause of dementia, is a complex disorder in which genetic and environmental factors interact. Three genes –the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and PSEN2)– have been linked to atusosomal dominant forms of AD. Besides, a fourth gene –the apolipoprotein E gene (APOE)– seems to be the only major genetic factor related to late-onset sporadic and familial AD cases. Although more than a thousand studies have been performed to date, little is known about other genetic factors leading to this devastating dementia. Nevertheless, the last three years have witnessed a surge in genetic research of AD due to the implementation of novel technologies enabling large-scale genetic analyses. Conclusion. This review provides a summary of current knowledge about AD in the genetic field (AU)

Modelos experimentales de la enfermedad de Alzheimer / Experimental models in Alzheimer´s disease

Introducción. La enfermedad de Alzheimer (EA) constituye la primera causa de demencia (60-80% del total). Su diagnóstico definitivo se realiza a través de los hallazgos anatomopatológicos de los cerebros de pacientes afectos. Desde los años 70 del pasado siglo se han desarrollado modelos experimentales que nos han permitido profundizar en su conocimiento y poner en marcha nuevas estrategias terapéuticas. Método. Se revisan todos los artículos publicados concernientes a modelos experimentales de EA, así como las nuevas estrategias terapéuticas basadas en ellos empleando la base de datos PubMed. Resultados. El objetivo de los modelos animales es conseguir replicar los síntomas y las lesiones responsables de la EA. Exsisten modelos animales basados en el metabolismo de la proteína precursora del amiloide (APP) (APP humana-wild type wt o las formas mutadas), otros basados en la presenilina (PS) (ratones transgénicos que sobreexpresan la forma wild-type o las mutadas), los dobles mutantes PS/APP. Otros basados en la proteína tau (tau-JNPL3) y los triple transgénicos PS/APP/tau. También se dispone de líneas con alteración de la expresión de la neprelisina, principal enzima en la degradación de Aß, así como de APOE. Otros modelos son la rata, el embrión de pollo, el perro, los cetáceos y los primates, los cultivos de neuronas hipocámpicas maduras y el efecto de los oligómeros de Aß sobre ellas (especies tóxicas solubles). Conclusiones. Los modelos experimentales suponen una herramienta decisiva para el conocimiento de las enfermedades neurodegenerativas como la EA. Además permiten el diseño de nuevas estrategias terapéuticas (AU)

Introduction: Alzheimer s disease (AD) is the most common neurodegenerative disease and (it accounts for 60-80 %). The certain diagnosis is made thanks to the brain patients study. Since 1970 there have been developed experimental models that have done a deep approach of this disease and new therapeutic researching. Methods: We review all the papers published about experimental models in AD, and all the new therapeutical approaches base don them using the database Pubmed. Results: Animal models aim to replicate the symptoms, the lesions or the cause(s) of AD. It has been described many experimental models in AD. There are animal models based on the metabolism of the amyloid precursor protein (APP) (human APPwild type wt- o the mutants forms), other based on Presenilin (PS) (transgenic mice that overexpress the form wild-type or the mutant ones), the double mutants PS/APP that develop the lesions earlier. There are other based on tau protein (tau-JNPL3) or the triple transgenic PS/APP/tau. There are also lines with altered expression of neprilysin, the main degrading enzyme of Abeta and also models based on APOE. Other models are rats, chick embryo, dog, primates and cetacean, cell culture of mature hippocampic neurons and the effects of the Abeta oligomers in them (soluble toxic species). Conclusions: Experimental models in AD have supposed a key tool in order to know deeply about neurodegenerative diseases, over all AD. Besides they allow us design new therapeutic approaches (AU)