Summary: Researchers discovered a powerful new drug target that could revolutionize how we treat Alzheimer’s disease. By focusing on an enzyme called IDOL, researchers found they could substantially reduce the buildup of toxic amyloid plaques in the brain.
Unlike current treatments that primarily focus on clearing existing plaques, targeting IDOL in neurons also lowers levels of the APOE protein—the strongest genetic risk factor for the disease—and boosts the brain’s natural resilience to cognitive decline. This multi-pronged approach not only clears the “trash” from the brain but also strengthens the connections between neurons, offering hope for a more effective way to freeze the disease’s progression.
Key Facts
- Targeting Neuronal IDOL: Removing the IDOL enzyme from brain neurons significantly reduces amyloid plaque load and improves communication between nerve cells.
- Resilience Booster: Deleting this enzyme increases the levels of receptors that regulate lipid metabolism, which has been shown to provide cognitive resilience even in patients with high plaque levels.
- APOE Reduction: The study found that targeting IDOL also lowers levels of APOE, the protein variant (APOE4) that serves as the most significant risk factor for late-onset Alzheimer’s.
Source: Indiana University
Indiana University School of Medicine scientists have identified a promising drug target for Alzheimer’s disease.
The team found that removing an enzyme from neurons in the brain substantially reduces amyloid plaques — a hallmark characteristic of the disease — and may provide further resilience against disease progression.
Over the past few years, the U.S. Food and Drug Administration has approved two disease-modifying drugs to treat Alzheimer’s disease. The drugs, lecanemab and donanemab, remove the buildup of amyloid plaques in the brain and can “freeze” a person in their current functional state.
The team of researchers at the IU School of Medicine, led by Hande Karahan, PhD, and Jungsu Kim, PhD, say targeting this enzyme, called IDOL, in neurons can be a new way to remove amyloid plaques and improve communication between neurons and lipid metabolism in the brain.
“What makes this exciting is that we now have a specific target that could lead to a new type of treatment,” said Kim, the P. Michael Conneally Professor of Medical and Molecular Genetics.
“We believe that IDOL will provide us with an alternative strategy to treat Alzheimer’s disease. Targeting enzymes in drug development offers key advantages due to their well-defined active sites or ‘pockets’ where drugs can attach and block their activity. This precision means we can design molecules that hit the right target with minimal side effects.”
In the study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the researchers generated two different animal models of Alzheimer’s disease by deleting the IDOL gene in the brain from either within neurons or microglia, the brain’s immune cells.
Karahan, assistant research professor of medical and molecular genetics, said they expected microglia to be the major driver of removing amyloid plaques because immune cells are key players in clearing amyloid and are the main cell type that produces IDOL in the brain.
Deletion of IDOL neurons not only reduced plaques, Karahan said, but it also reduced levels of a protein called apolipoprotein E, or APOE, that is associated with Alzheimer’s disease; one of the protein’s variants, APOE4, is the strongest risk factor for late-onset Alzheimer’s disease. APOE also plays a critical role in lipid metabolism, Karahan said.
The team also discovered that levels of receptors that can regulate APOE and amyloid plaques in the brain increased when the enzyme was removed from neurons.
These receptors have a critical role in lipid metabolism and healthy neuronal communication. Karahan said a recent study shows that activating a pathway, which is also regulated by these receptors, provides resilience to cognitive decline in Alzheimer’s patients who have high amounts of plaques.
“This is especially important from a clinical perspective because patients are usually diagnosed with the disease after accumulating substantial amyloid plaque load in the brain. Not only decreasing amyloid levels but also increasing resilience to these pathological changes could maximize clinical benefits,” Karahan said.
“Targeting neuronal IDOL may offer multiple therapeutic benefits in Alzheimer’s disease by simultaneously reducing amyloid burden while enhancing neuroprotective effects.”
Kim said the team will next work on a few strategies targeting the enzyme to develop drugs for treating Alzheimer’s disease, adding it’s important to assess the safety of compounds and their functional effects in preclinical models. Kim said they’ll also determine whether IDOL inhibition preserves synaptic connections and mitigates tau pathology in Alzheimer’s disease.
Key Questions Answered:
A: While current drugs like lecanemab and donanemab focus on clearing existing plaques, targeting the IDOL enzyme does something extra: it builds resilience. It’s like not only taking out the trash but also upgrading the building’s security system. By improving lipid metabolism and neuronal communication, this method helps the brain stay functional even if some plaques remain.
A: APOE4 is the strongest genetic risk factor for Alzheimer’s. This study discovered that removing the IDOL enzyme naturally lowers APOE levels. By hitting both the plaques and the underlying genetic risk protein simultaneously, researchers may have found a way to attack the disease from two sides at once.
A: That’s the goal. Because IDOL is an enzyme with a well-defined “pocket” where a drug can attach, it is a perfect candidate for drug development. Scientists are now working on molecules that can block this enzyme’s activity, which could eventually lead to a treatment that is more precise and has fewer side effects than current options.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease and neuropharmacology research news
Author: Rory Appleton
Source: Indiana University
Contact: Rory Appleton – Indiana University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Deletion of neuronal Idol ameliorates Alzheimer’s disease–related pathologies via APOE receptors” by Hande Karahan, Kelly Hartigan, Md Mamun Al-Amin, Sutha K. John, Brianne McCord, H. R. Sagara Wijeratne, Dominic J. Acri, Daniel C. Smith, Luke C. Dabin, Hannah M. Rondon Cordero, Byungwook Kim, Do-Hun Lee, Jungsu Kim. Alzheimer’s & Dementia
DOI:10.1002/alz.70949
Abstract
Deletion of neuronal Idol ameliorates Alzheimer’s disease–related pathologies via APOE receptors
INTRODUCTION
Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology.
METHODS
To investigate the cell-type–specific role of IDOL, we generated Idol conditional knockout mice on an Aβ-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses.
RESULTS
We demonstrated that neuronal, but not microglial, Idol deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL-LDLR in amyloid pathology. In addition, neuronal Idol deletion increased the levels of Reelin receptors important for synaptic function, and single-nuclei RNA sequencing revealed significant changes associated with synaptic organization.
DISCUSSION
Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer’s disease pathogenesis by regulating the levels of brain APOE receptors.
