Human Brain Signals Connection Concept Illustration

Un nuevo estudio cuestiona las creencias generalizadas sobre el alzhéimer


Un nuevo estudio cuestiona el dogma detrás de los ensayos de medicamentos para el Alzheimer.

El estudio descubrió que a medida que avanza la enfermedad de Alzheimer, disminuyen los niveles cerebrales de enzimas que regulan el plegamiento del ADN.

Investigadores de la Universidad de Pittsburgh, la Universidad McGill y la Universidad de Harvard descubrieron que, a diferencia de investigaciones anteriores, los niveles de enzimas cerebrales que controlan[{” attribute=””>DNA folding drop as Alzheimer’s disease worsens. Their findings were recently published in the journal Nature Communications.

These dogma-challenging findings show that decreased levels of Histone Deacetylase I (HDAC I), one of the enzymes that control how DNA is packaged inside the cell’s nucleus, are associated with the negative effects of misfolded beta-amyloid and tau proteins and Alzheimer’s disease-associated cognitive decline. These results were verified across two independent cohorts of live patients with Alzheimer’s disease as well as on post-mortem brain tissues.

Importantly, the new findings imply that using HDAC inhibitors—drugs that reduce HDAC levels and are presently being tested in clinical trials for mild Alzheimer’s disease—may be harming rather than benefiting patients.

HDAC Levels Brain

HDAC levels are reduced in the brains of older adults with Alzheimer’s disease compared to healthy older adults. Credit: Tharick Pascoal

“Approximately one-third of elders who have brain amyloid pathology do not develop Alzheimer’s disease,” said lead author Tharick Pascoal M.D.  He is also an assistant professor of psychiatry and neurology at Pitt’s School of Medicine. He continues, “Now we have evidence of another factor that dictates whether or not the disease will progress further, and it is related to how the brain environment can affect the expression of our genes.”

Alzheimer’s disease is a deadly neurodegenerative disease that typically affects the elderly but begins decades before symptoms appear. Forty-four million people live with Alzheimer’s disease or associated dementia. Alzheimer’s patients develop cognitive impairments over time, including memory loss and difficulty thinking and speaking, due to the formation of plaques of misfolded beta-amyloid and tangled strands of tau proteins, which induce nerve cell death and brain tissue damage.

However, amyloid and tau disorders are just one piece of the complex picture. Over the last few decades, researchers have started to focus on additional processes—neuroinflammation and changes in the chemical environment of the brain cells—and how these might impact the development of the condition.

One of these processes is known as epigenetic histone modification. A cell may adjust the efficiency with which genetic information is translated into templates for new proteins by modifying how DNA is folded within its nucleus—whether it is tightly wrapped around protein barrels called histones or hung in looser threads. This permits the cell to swiftly and reversibly modify the way our genes operate and react to changes in the environment without changing the DNA sequence itself.

In the long quest to develop safe, effective therapies that stave off cognitive decline and reverse disease progression, a subtype of enzymes that drive epigenetic modifications—HDACs—emerged as promising targets for new Alzheimer’s therapies.

HDACs carry on a chemical reaction that encourages tighter packing of DNA molecules into condensed bundles and restricts biosynthesis of new proteins in response to environmental cues.

Earlier studies on post-mortem brain samples reported that levels of HDACs in the brains of patients with Alzheimer’s increase as the disease progresses. High levels of HDACs were thought to restrict the brain’s ability to produce new functional proteins that make up critical cell components and, therefore, contribute to memory loss and cognitive decline.

The new paper, however, challenges the status quo and adds another piece to an already confusing picture. The loss of HDAC I might be mechanistically linked with the emergence of beta-amyloid and tau pathologies—which, as Pascoal and colleagues showed in their previous paper, are intertwined with brain tissue inflammation and drive Alzheimer’s disease progression—and precede cognitive changes that accompany the disease.

To ensure that their findings represented the real picture across a diverse patient pool, researchers ran two parallel but entirely independent studies at McGill University in Canada and Massachusetts General Hospital, enrolling 94 participants in total. The two sites did not communicate throughout the study period and presented their results unaware of the other group’s findings.

Using a selective molecular tracer called [11C]Martinostat, los investigadores demostraron que los niveles de HDAC I se redujeron considerablemente en los cerebros de las personas con la enfermedad de Alzheimer en comparación con los controles sin Alzheimer, específicamente en las regiones enterradas en el interior del núcleo del cerebro (el hipocampo y la línea media), así como en la corteza temporal del cerebro.

Los análisis mostraron que la HDAC I reducida en las áreas del cerebro que son más susceptibles a los cambios degenerativos asociados con la enfermedad de Alzheimer correspondía a una mayor carga de beta-amiloide y tau. También predijo la neurodegeneración progresiva y el deterioro cognitivo durante un período de dos años.

Si bien los investigadores confían en que los rigurosos procesos que rigen el diseño de los ensayos clínicos garantizan los más altos estándares de seguridad del paciente, advierten que los esfuerzos para probar los inhibidores de HDAC podrían estar mal dirigidos. En cambio, dicen, el campo necesita explorar más a fondo la relación entre la activación de HDAC y la progresión de la enfermedad y determinar qué clase específica de HDAC, de un total de 18, juega un papel clave en la patología cerebral relacionada con la enfermedad de Alzheimer.

Aún así, los científicos son optimistas.

“La buena noticia es que, por naturaleza, los procesos epigenéticos son cambiantes”, dijo Pascoal. “Hay mucha esperanza para futuros tratamientos, y una combinación de terapias anti-amiloide con medicamentos que pueden rescatar la pérdida de HDAC es muy prometedora”.

Referencia: “[11C]El análisis PET de Martinostat revela una disponibilidad reducida de HDAC I en la enfermedad de Alzheimer” por Tharick A. Pascoal, Mira Chamoun, Elad Lax, Hsiao-Ying Wey, Monica Shin, Kok Pin Ng, Min Su Kang, Sulantha Mathotaarachchi, Andrea L. Benedet, Joseph Therriault , Firoza Z. Lussier, Frederick A. Schroeder, Jonathan M. DuBois, Baileigh G. Hightower, Tonya M. Gilbert, Nicole R. Zürcher, Changning Wang, Robert Hopewell, Mallar Chakravarty, Melissa Savard, Emilie Thomas, Sara Mohaddes, Sarah Farzin, Alyssa Salaciak, Stephanie Tullo, A. Claudio Cuello, Jean-Paul Soucy, Gassan Massarweh, Heungsun Hwang, Eliane Kobayashi, Bradley T. Hyman, Bradford C. Dickerson, Marie-Christine Guiot, Moshe Szyf, Serge Gauthier, Jacob M Hooker y Pedro Rosa-Neto, 19 de julio de 2022, Comunicaciones de la naturaleza.
DOI: 10.1038/s41467-022-30653-5

El estudio fue financiado por la Asociación de Alzheimer, el Instituto del Cerebro de Weston, los Institutos Canadienses de Investigación en Salud, el Fonds de Recherche du Quebec–Sant y los Institutos Nacionales de Salud.

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