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Unraveling the Mysteries of Alzheimer’s Disease

Research AD

Three new studies under way in the laboratory of Claudio Soto, Ph.D., are investigating potential new ways to diagnose and treat Alzheimer’s disease (AD). Dr. Soto directs a team of researchers focused on the investigation of the molecular basis of protein misfolding disorders, mainly Alzheimer’s disease and prion-related disorders.

“A hallmark event in Alzheimer’s disease is the misfolding of the amyloid-beta protein, which then is deposited in the brain in the form of amyloid plaques,” says Dr. Soto, a professor in the department of Neurology at McGovern Medical School at UTHealth. “These plaques, or some of the precursor misfolded oligomeric particles, are thought to cause neuronal death and synaptic loss resulting finally in dementia.”

Translating Research into Diagnostic Tools and Treatments

Over the past 20 years, Dr. Soto has focused his research on understanding the mechanism and factors involved in the conversion of a normal protein into the disease-associated abnormal form that accumulates in the brain to produce some of the most devastating neurodegenerative diseases. “Our studies combine basic science investigations with a permanent effort to translate these discoveries into novel approaches for early diagnosis and treatment,” he says.

With a new grant from the National Institutes of Health, Dr. Soto and his team are investigating a blood-based diagnosis for AD. A fast-track combined Phase I and II Small Business Technology Transfer (STTR) project in partnership between Amprion, Inc. and McGovern Medical School at UTHealth, the project may offer a way to diagnose AD before extensive brain damage and dementia set in.

“For this purpose we’re adapting the protein misfolding cyclic amplification (PMCA) technology invented in our lab for specific and highly sensitive detection of misfolded Aβ oligomers in human blood,” Dr. Soto says. “Aβ oligomers may be circulating in the body years, if not decades, before cognitive symptoms arise. We’re hoping the results generated by this project will detect them and lead to the first biochemical test for blood-based diagnosis of AD.”

Dr. Soto is also principal investigator in two studies funded by UTHealth Brain Initiative Awards: “Chimeric Mice Harboring Human Nerve Cells as a Model of Alzheimer’s Disease” and “Traumatic Brain Injury Promotes Alzheimer’s Disease Through Seed Formation.” The first study, conducted in collaboration with Brian Davis, Ph.D., of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, aims to develop new models of AD by grafting into the mouse brain humanderived cells from healthy individuals, as well as from AD patients affected by inherited and sporadic forms of the disease. Human nerve cells have been generated in Dr. Soto’s lab by reprogramming adult fibroblasts into induced pluripotent stem cells. They are later converted into different types of neurons.

“Our working hypothesis is that chimeric mice harboring human nerve cells will reproduce the complete cerebral abnormalities observed in AD patients,” he says. “As a result, chimeric mice may be more relevant and predictable models of AD and may become great tools to investigate the molecular bases of neurodegenerative processes. This model may also help us discover new pharmaceutical targets and biomarkers for the much-needed development of new drugs to treat or even prevent the onset of the disease.”

In the second UTHealth Brain Initiative study, Dr. Soto and his team, in collaboration with Pramod Dash, Ph.D., of the Vivian L. Smith Department of Neurosurgery, posit that traumatic brain injury induces the formation of the first misfolded oligomeric seeds composed of either or both amyloid-beta and tau protein, which then spread the pathology throughout the brain by a prion-like mechanism, resulting in the development of AD. They will test the theory in various transgenic mice models.

The research has the potential to change the face of diagnosis and treatment of Alzheimer’s disease. “Alzheimer’s disease is the most common form of dementia in late life, and at present it does not have a cure or an effective treatment,” Dr. Soto says. “It is a leading cause of death in the developed world and currently affects more than 10 million people worldwide. Its treatment is hampered by the lack of early, sensitive and objective laboratory tests. We hope to change that.”