Enfermedad de Alzheimer: hacia el diseño racional de una vacuna eficaz / Alzheimer's disease: toward the rational design of an effective vaccine

The promising clinical results with the human monoclonal antibodies aducanumab and solanezumab targeting β-amyloid in AlzheimerÆs disease treatment, confirm both the amyloid cascade hypothesis and protective natural immunity, while strengthening the immunotherapeutic approach. That aducanumab recognizes a conformational epitope formed by oligomers emphasizes the need for whole β-amyloid, not just its B-cell epitopes as have been the norm to avoid pro-inflammatory Th1-reactions.That truncated β-amyloid having N-terminal pyroglutamate is present only in diseased brain simples a new useful vaccine antigen. Another relevant antigen is the tau protein, which shows a close association and cooperativity with β-amyloid in exacerbating this disease. Hence, effective vaccines may be polyvalent, presenting to the immune system a number of antigens relevant to induce an immune response to prevent or slowdown the onset of this disease. The presence of both B and T cell epitopes in the antigens, require a sole Th2 immunity to avert brain inflammation; a task that cannot be attain with adjuvants that under any conditions induce Th1 and/or Th17 immunities. Hence, new vaccine adjuvants are need to safely induce Th2 while inhibiting Th1 immunity, an objective that can be achieved with certain fucosylated glycans or triterpene glycosides, which apparently bind to the DC-SIGN lectin on dendritic cells polarizing the immune response toward Th2 immunity. Because the triterpene glycosides have the pharmacophore needed to co-stimulate T cells, they may ameliorate the T-cell anergy associated with immunosenescence and responsible for poor vaccine efficacy in the elderly population, a critical issue for an AlzheimerÆs vaccine...

Los resultados prometedores en el tratamiento de la enfermedad de Alzheimer con Aducanumab y Solanezumab, anticuerpos monoclonales humanos contra β-amiloide, ratifican la hipótesis de la cascada del amiloide y la existencia de inmunidad natural contra Alzheimer, mientras refuerza el método inmunoterapéutico. Que Aducanumab reconoce un epίtopo conformacional formado por oligómeros, acentúa la necesidad del β-amiloide completo y no solo sus epίtopos de células B, como ha sido la norma para evitar reacciones pro-inflamatorias Th1. De que el β-amiloide truncado con piroglutamato en su extremo N-terminal se encuentra solo en cerebros enfermos, es un antígeno útil; otro antígeno importante es la proteína tau, que tiene una estrecha asociación y cooperatividad con β-amiloide en exacerbar esta enfermedad. Una vacuna eficaz puede ser polivalente para presentar al sistema inmunológico una variedad de antígenos importantes e inducir una respuesta para prevenir o retardar el comienzo de esta enfermedad. La necesidad de epítopos de células B y T en los antígenos, implica una inmunidad tipo Th2 para evitar inflamación del cerebro; objetivo que no se puede alcanzar con adyuvantes que inducen inmunidades Th1 y/o Th17. Consecuentemente, se necesitan nuevos adyuvantes de vacunas para inducir sin riesgos la inmunidad Th2 mientras se inhibe la Th1, objetivo que se puede lograr con ciertos glicanos fucosilados o glucósidos triterpénicos que se unen a la lectina DC-SIGN en células dendríticas, polarizando la respuesta hacia la inmunidad Th2. Como los glucósidos triterpénicos tienen el farmacóforo necesario para co-estimular las células T, podrán moderar la anergia de las células T asociada con immunosenescencia, responsable por la baja eficacia de las vacunas en la población anciana, materia critica para vacunas contra la enfermedad de Alzheimer...

Cien años de la enfermedad de Alzheimer: La inmunoterapia ¿una esperanza? / One hundred years of Alzheimer's disease: Immunotherapy a hope?

In 1906 Alois Alzheimer, described the cerebral lesions characteristic of the disorder that received his name: senile plaques and neurofibrillary tangles. Alzheimer's disease (AD) is now, 100 years after, the most prevalent form of dementia in the world. The longer life expectancy and aging of the population renders it as a serious public health problem of the future. Urgent methods of diagnosis and treatment are required, since the definitive diagnosis of AD continues to be neuropathologic. In the last 30 years several drugs have been approved to retard the progression of the disease; however, there are still no curative or preventive treatments. Although still in experimentation, the visualization of amyloid deposition by positron emission tomography or magnetic resonance imaging will allow in vivo diagnosis of AD. In addition, experiments with the amyloid vaccine are still ongoing, and very recent data suggest that intravenous gammaglobulins may be beneficial and safe for the treatment of AD.

Advances in molecular biology and clinical study of amyloid precursor protein for Alzheimer's disease / 中国医学科学院学报

Alzheimer's disease (AD) is the most common cause of dementia in elderly population. There are two hallmark pathological lesions: the intracellular neurofibrillary tangles (NFTs) and the extracellular amyloid deposits in the senile plaques (SP). The NFTs are aggregates of hyperphosphorylated microtubule Tau protein. The amyloid deposits in the SP are the beta-amyloid (Abeta) peptides-Abeta40 and Abeta42. The Abeta peptides are derived from the amyloid precursor protein (APP) which is considered very important for the AD pathogenesis. In recent years, studies have focused on understanding the generation of Abeta peptides by the alpha-, beta- and gamma- secretase activity on APP, as cause and progression of both familial and sporadic AD (FAD and SAD). This review covers the trafficking and processing of APP, the amyloid cascade hypothesis in AD pathogenesis, the mutations in the genes encoding APP, PS1 and PS2 of early-onset and late-onset AD. The risk factor apolipoprotein E (ApoE) for AD and therapeutic anti-beta-amyloid vaccination strategies for prevention of AD are also discussed.