Breakthrough Discovery: Early Treatment for Alzheimer’s Could Change Lives Forever!
Alzheimer’s early treatment discovery
New Breakthrough: Scientists Find Key to Reversing Early Alzheimer’s
Scientists have uncovered that targeting a specific class of sugar-modified proteins can boost cell repair, regenerate lost neurons, and reverse cellular changes associated with neurodegenerative conditions.
In a groundbreaking study from Penn State, researchers revealed that focusing on a distinct set of proteins responsible for cell repair regulation and growth promotion may offer a new approach to combat Alzheimer’s and similar diseases.
The team discovered that disrupting the sugar modifications on these proteins enhances cellular repair and reverses the abnormalities commonly seen in these conditions.
The findings, recently published in iScience, are protected by a patent.
“Most Alzheimer’s treatments focus on pathological changes that appear in the late stages of the disease,” noted Scott Selleck, a biochemistry and molecular biology professor at Penn State and the study’s lead investigator.
“While recently approved drugs by the U.S. FDA slow the disease progression by targeting amyloid accumulation, we believe targeting earlier cellular deficits may provide tools to halt or even reverse the disease process. Our research focuses on early cellular changes that occur not only in Alzheimer’s but also in diseases like Parkinson’s and ALS.”
An estimated 6.9 million Americans aged 65 and above live with Alzheimer’s, according to the Alzheimer’s Association. Despite its prevalence, the exact biological causes of the disease remain elusive.
Heparan sulfate-modified proteins, involved in cell signaling, have been implicated in Alzheimer’s development, though their precise role is still unclear. In this study, human and mouse brain cells exhibiting Alzheimer’s traits were analyzed, demonstrating that these proteins regulate key cellular processes affected in multiple neurodegenerative disorders.
Alzheimer’s early treatment discovery: Role of Heparan Sulfate-Modified Proteins
Heparan sulfate-modified proteins reside on the surface of animal cells and within the extracellular matrix. These proteins are characterized by heparan sulfate, a sugar polymer rich in sulfate groups.
The attachment of these chains allows the proteins to form signaling complexes that govern cell growth and interaction with their surroundings. These pathways also regulate autophagy, a crucial process for cellular repair by removing damaged components.
“Autophagy is impaired in the early stages of many neurodegenerative diseases, leading to diminished repair capacity,” explained Selleck. “Our study revealed that heparan sulfate-modified proteins inhibit autophagy-dependent repair. Moreover, disrupting these sugar modifications boosts autophagy, allowing cells to better address damage.”
In both human and mouse cells, reducing the activity of these proteins also alleviated other early-stage pathologies of neurodegenerative diseases, including improving mitochondrial function and reducing the accumulation of fatty compounds within cells.
The team further investigated these proteins in an Alzheimer’s model using fruit flies with presenilin protein deficits, which cause early-onset disease in both humans and flies.
In flies with presenilin mutations, reducing the function of heparan sulfate chains prevented neuronal death and corrected additional cellular defects, aligning with recent human genetics research.
“People who carry mutations in the PSEN1 gene typically develop Alzheimer’s in their mid-40s. However, inheriting a rare variation in the APOE protein, which binds to heparan sulfate, can delay the disease by decades,” said Selleck.
“This research builds on recent findings, directly implicating heparan sulfate in the pathology associated with PSEN1 and APOE. Targeting the enzymes that produce heparan sulfate could potentially halt neurodegeneration in humans.”
These collective findings suggest that disrupting the structure of heparan sulfate modifications may block or reverse early cellular dysfunctions in Alzheimer’s models.
Alzheimer’s early treatment discovery: Implications for Broader Treatment
“We successfully prevented neuron loss, corrected mitochondrial defects, and improved behavioral outcomes, all indicative of restored nervous system function,” said Selleck. “These findings point to a promising target for future treatments, aiming to reverse the earliest cellular changes found in various neurodegenerative diseases.”
The research team also investigated how gene expression shifts when the capacity to produce heparan sulfate chains is eliminated in human cells.
They discovered that over 50% of approximately 70 genes associated with late-onset Alzheimer’s were altered, including the APOE gene, linking these proteins to both common and late-onset forms of the disease.
“There’s a critical need to understand and treat the earliest cellular changes in disease progression,” Selleck emphasized.
“We’ve shown that targeting a single class of proteins—those modified by heparan sulfate—can address common neurodegenerative disease features like reduced autophagy, mitochondrial dysfunction, and lipid build-up. These proteins represent a promising direction for drug development.”
The researchers also believe that manipulating this pathway to enhance cellular repair systems could be relevant for other diseases where autophagy defects play a role.
“The potential applications of this pathway could extend across numerous medical conditions,” Selleck added.
Study Reference:
“Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease” by Nicholas Schultheis, Alyssa Connell, Alexander Kapral, Robert J. Becker, Richard Mueller, Shalini Shah, Mackenzie O’Donnell, Matthew Roseman, Lindsey Swanson, Sophia DeGuara, Weihua Wang, Fei Yin, Tripti Saini, Ryan J. Weiss, and Scott B. Selleck, published July 2, 2024, in iScience. DOI: 10.1016/j.isci.2024.110256.
The research team from Penn State included co-authors Nicholas Schultheis, a doctoral student in biochemistry, microbiology, and molecular biology; research assistant Alyssa Connell; and undergraduate students Richard Mueller, Alexander Kapral, Robert Becker, Shalini Shah, Mackenzie O’Donnell, Matthew Roseman, Lindsey Swanson, and Sophia DeGuara. Collaborators also included Weihua Wang, Associate Professor Fei Yin from the University of Arizona, and Ryan Weiss, Assistant Professor of Biochemistry and Molecular Biology, and graduate student Tripti Saini from the University of Georgia.
This study was supported by funding from the National Institutes of Health and Penn State Eberly College of Science.
