Genetic detective work by Brigham researchers has revealed a promising new therapy method for Alzheimer’s.
The severity, age of onset, and presentation of Alzheimer’s disease (AD) vary widely among individuals. The SORL1 gene has recently drawn more interest since mutations in this gene appear to have a link to both early and late onset of the disease. However, it is unclear how SORL1 damage results in the condition.
Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham health care system, discovered that loss of normal SORL1 function results in a reduction in two crucial proteins known to be involved in Alzheimer’s and which play a crucial role in the neurons of healthy people . They performed their research using stem cells from Alzheimer’s patients. Their findings, published in Cell Reports, point to a potential new treatment plan, particularly for patients who don’t respond to current medications.
The Research Findings
To shed light on a different disease-causing route, the researchers in this new study used a stem-cell-based methodology to evaluate natural genetic variability in Alzheimer’s patients. Progenitor stem cells taken from individuals in two Alzheimer’s research cohorts, the Religious Order Studies and the Rush Memory and Aging Project, were modified using CRISPR technologies to eliminate the SORL1 gene.
They next manipulated the stem cells to differentiate into four different types of brain cells to investigate the effect of SORL1 deletion on each cell type. The brain’s “support” cells, astrocytes, and neurons both exhibited the most notable impact. Two essential proteins associated with Alzheimer’s, APOE and CLU, were found to be significantly reduced in two distinct ways in neurons missing SORL1.
Without APOE and CLU, neurons cannot control lipid accumulation in droplets, which could disrupt the communication between neurons. The researchers confirmed their laboratory-based findings by analyzing the natural genetic variation in SORL1 expression in the brain tissue of 50 cohort members. They discovered that lower SORL1 activity in neurons was again connected with lower levels of APOE and CLU in these individuals.
In the past, scientists have focused on three prominent genetic factors (APP, PSEN1, and PSEN2), the mutations of which frequently result in hereditary, early-onset Alzheimer’s (diagnosis before age 65).
Even though in many cases of late-onset (“sporadic”) Alzheimer’s, a more complicated interaction between genes, lifestyle, and environment defines the presentation of the illness, preclinical models and cell-based systems heavily rely on mutations in these genes to represent the disease. Individual differences also exist in important neurological aspects of Alzheimer’s, such as the prevalence of amyloid-beta plaques in the brain.
New Targets for Alzheimer’s Treatment: What’s Next?
Researchers from Brigham performed a pioneering role in figuring out the chemical and genetic causes of Alzheimer’s disease, including significant improvements in our understanding of the amyloid molecule. Aducanumab and lecanemab, two novel anti-amyloid treatments, have gained accelerated and traditional approval from the US Food and Drug Administration, respectively. However, not all patients respond to these medications, necessitating the need for additional therapy choices.
The corresponding author of the study, Tracy Young-Pearse of the Ann Romney Center for Neurological Diseases, said their study is one of the first to use human cells from a large number of people to try to comprehend the ‘molecular road’ that begins with SORL1 and coincides with APOE.
She further stated that these results highlight the significance of developing therapies that target these and other biological pathways to Alzheimer’s. The more we understand the distinctions between subtypes of the disease, the more we will be able to devise sensible therapeutic strategies to try to fix the problem that is predominantly driving the condition in each patient.
The researchers are continuing to investigate alternative routes that may lead to Alzheimer’s, including those involving microglia (brain cells that perform immunological activities). The researchers seek to find additional molecular pathways crucial in Alzheimer’s by using study models and procedures representative of the disease presentation in the general population.
- Lee, H., Aylward, A.J., Pearse, R.V., Hsieh, Y.C., Augur, Z.M., Benoit, C.R., Chou, V., Knupp, A., Pan, C., Goberdhan, S. and Duong, D.M., 2023. Cell-type-specific regulation of APOE levels in human neurons by the Alzheimer’s disease risk gene SORL1. bioRxiv, pp.2023-02.
- The road that ends with Alzheimer’s. The Harvard Gazette. https://news.harvard.edu/gazette/story/2023/08/molecular-road-to-alzheimers-leads-to-new-treatment-strategy/. Published Online: 22nd August, 2023. Accessed: 4th October, 2023.
- Stem cell research sheds light on new ‘molecular road’ to Alzheimer’s disease. Medical Press. https://medicalxpress.com/news/2023-08-stem-cell-molecular-road-alzheimer.html. Published Online: 22nd August, 2023. Accessed: 4th October, 2023.
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