Recent Research Unveils a Novel Pathway to Alzheimer’s Disease at the Molecular Level
A fresh perspective on the intricacies of Alzheimer’s Disease (AD) has emerged through the diligent efforts of researchers, shedding light on a hitherto unexplored avenue linked to the ailment. Specifically, the SORL1 gene’s role in AD patients has come under scrutiny, revealing that damage to this gene leads to a decline in two pivotal proteins crucial for maintaining the health of neurons. Employing innovative stem-cell-based techniques, these findings offer a potential alternative approach for treating AD, especially for individuals who exhibit resistance to existing therapeutic methods.
The scientific detectives at Brigham have embarked on a genetic quest that unveils a promising avenue for tackling Alzheimer’s disease. AD, characterized by a wide spectrum of age-related onsets, symptoms, and severity levels, has recently turned the spotlight on the SORL1 gene due to its connection with both early and late stages of the disease. Nevertheless, the precise ramifications of SORL1 damage on the progression of AD have remained enigmatic.
Through the utilization of stem cells obtained from AD patients, the investigators hailing from Brigham and Women’s Hospital, an integral part of the Mass General Brigham healthcare network, have discerned that the loss of normal SORL1 function precipitates a reduction in two pivotal proteins intricately associated with AD. These proteins play a fundamental role in the neurons of healthy individuals. Their meticulous research, documented in the journal Cell Reports, introduces a potentially groundbreaking strategy for treating AD, particularly catering to patients who do not respond favorably to current therapeutic regimens.
Tracy Young-Pearse, PhD, a notable figure from the Ann Romney Center for Neurological Diseases and the corresponding author of the study, underlines the nascent nature of understanding the various subtypes of AD within the realm of neurological research. She emphasizes the pursuit of precision neurology, aiming to accurately predict the responsiveness of patients to treatment strategies that target specific genes or address the issues they give rise to.
Traditionally, the focus of AD research has gravitated towards three potent genetic triggers (APP, PSEN1, and PSEN2) that commonly undergo mutations in cases of hereditary, early-onset AD (diagnosed before the age of 65). Preclinical models and cell-based systems have primarily centered around mutations in these genes to mimic AD, even though late-onset (“sporadic”) AD in many cases results from intricate interactions among genes, lifestyle, and the environment, thereby influencing the presentation of the disease. Furthermore, key neurological features of AD, including the accumulation of amyloid-beta plaques in the brain, exhibit variability across different individuals.
Brigham’s researchers have taken the helm in unraveling the molecular and genetic underpinnings of AD, with significant breakthroughs related to the amyloid protein. Two novel anti-amyloid therapies, aducanumab and lecanemab, have obtained approval from the United States Food and Drug Administration, yet the efficacy of these drugs varies among patients, necessitating the exploration of alternative treatment avenues.
The present study employs a cutting-edge approach rooted in stem cells, delving into the natural genetic diversity present in AD patients to uncover an alternate route driving the disease. By utilizing CRISPR technologies, the researchers successfully removed the SORL1 gene from stem cells derived from participants in two Alzheimer’s research groups: the Religious Order Studies and Rush Memory and Aging Project. These stem cells were then directed to differentiate into four distinct types of brain cells to ascertain the impact of SORL1 removal on each cell type. The most substantial consequences were observed in neurons and a supportive brain cell type known as astrocytes. Neurons lacking SORL1 exhibited a significant reduction in the levels of two crucial AD-associated proteins: APOE and CLU.
The absence of APOE and CLU hindered neurons’ ability to regulate lipids effectively, leading to the accumulation of lipid droplets that potentially impede communication between neurons. The researchers corroborated their laboratory findings by studying the natural genetic variations in SORL1 expression within the brain tissue of 50 individuals from the research groups. Once again, a correlation emerged between lower SORL1 activity in neurons and reduced levels of APOE and CLU in these individuals.
The researchers are unwavering in their commitment to exploring additional pathways that may contribute to AD, including those involving microglia—brain cells responsible for immune functions. By adopting research models and methodologies that faithfully mirror the presentation of AD in the general population, the team hopes to uncover more biological pathways of significance in the context of AD.
The distinguished hospitals under Mass General Brigham’s banner boast a storied legacy of medical breakthroughs, spanning from the inaugural use of ether in surgery at Massachusetts General Hospital to the world’s pioneering successful organ transplant at Brigham and Women’s Hospital. Nearly every medical treatment, test, drug, or device in use today stems from fundamental research discoveries and translational advancements. Young-Pearse and her colleagues aspire to extend this tradition of enhancing patient care through their research endeavors.
Young-Pearse elaborates that their study stands as one of the pioneering efforts to comprehend the “molecular road” initiated by SORL1, a pathway that intriguingly converges with APOE. The insights garnered from their research point to the significance of developing interventions targeting these molecular routes, among others, to combat Alzheimer’s disease. This approach aligns with the overarching objective of grasping subtype-specific distinctions within AD, ultimately facilitating the design of rational therapeutic interventions tailored to address the primary driving factors of the disease in each patient.
Reference: “Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1” by Hyo Lee, Aimee J. Aylward, Richard V. Pearse, Alexandra M. Lish, Yi-Chen Hsieh, Zachary M. Augur, Courtney R. Benoit, Vicky Chou, Allison Knupp, Cheryl Pan, Srilakshmi Goberdhan, Duc M. Duong, Nicholas T. Seyfried, David A. Bennett, Mariko F. Taga, Kevin Huynh, Matthias Arnold, Peter J. Meikle, Philip L. De Jager, Vilas Menon and Tracy L. Young-Pearse, 22 August 2023, Cell Reports.
DOI: 10.1016/j.celrep.2023.112994
The research received funding from the National Institutes of Health.
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Frequently Asked Questions (FAQs) about Neurological Insights
What is the focus of the recent research on Alzheimer’s Disease?
The recent research delves into uncovering a new “molecular road” in Alzheimer’s Disease (AD), specifically examining the role of the SORL1 gene and its impact on key neuronal proteins.
What are the key findings of the study?
The study highlights that damage to the SORL1 gene in AD patients leads to a reduction in essential proteins crucial for maintaining healthy neurons, providing insights into potential alternative treatments for AD.
How was the research conducted?
Researchers employed stem-cell-based techniques, using stem cells from AD patients. They removed the SORL1 gene and observed its effects on various types of brain cells, particularly neurons and astrocytes, shedding light on the reduction of AD-associated proteins.
What significance does the SORL1 gene hold in Alzheimer’s Disease?
The SORL1 gene has drawn attention due to its links with both early and late-stage AD. However, the precise impact of SORL1 damage on the disease was previously unclear.
How might this research influence AD treatment?
The findings offer a potential strategy for AD treatment, particularly for patients who don’t respond to current therapies. The study emphasizes a precision neurology approach for more targeted treatment interventions.
Are there any other pathways explored in AD research?
The researchers are also investigating other pathways, including those involving microglia, in their pursuit of a comprehensive understanding of the disease and potential avenues for intervention.
What is the broader impact of this research?
The study contributes to our understanding of AD’s complex molecular underpinnings, aiding in the design of rational therapeutic strategies that address the specific factors driving the disease in individual patients.
More about Neurological Insights
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- Brigham and Women’s Hospital
- Mass General Brigham
- Alzheimer’s Association
- National Institutes of Health
- Precision Neurology Approach
- CRISPR Technologies
