Alzheimer’s disease (AD) is a neurological condition that leads to progressive memory loss and cognitive decline. It is also considered the leading cause of dementia among neurodegenerative disorders. A hallmark of Alzheimer’s disease is the accumulation of amyloid beta and tau proteins in the brain, and the pathology is associated with chronic inflammation and disruption of the blood–brain barrier, contributing to further brain damage.
Current medications, including some neuronal activity inhibitors, provide only modest symptomatic relief. They do not halt disease progression, and tend to lose effectiveness over time. Two disease-modifying therapies approved in recent years and currently in use (lecanemab and donanemab) are monoclonal antibodies designed to bind to amyloid beta and reduce its buildup; however, clinical trials have shown mixed results in terms of cognitive improvement, and some patients have experienced serious adverse effects, including brain edema. Altogether, these challenges underscore the pressing need for safer and more effective treatments for a disease that is expected to affect 82 million people age 65 and older by 2050 in the United States alone.
In search of an innovative medicine, a group of scientists at Jinan University in Guangdong, China, has developed a disease-modifying therapy that, when tested in a non-human primate Alzheimer’s model, has shown improvements in both biological markers and clinical aspects of the disease. “These outcomes offer new hope for the tens of millions of Alzheimer’s patients worldwide,” says Wenliang Lei, principal investigator at Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR) in Jinan University, and co-corresponding author of the study published in Advanced Science.
Exploring Innovative Approaches to Neuro-regeneration
One of the key problems in Alzheimer’s disease is the progressive loss of neurons. The brain is made up of neurons and glial cells, the latter of which support neurons in various ways and also act as the brain’s immune cells. Glial cells include astrocytes and microglia and, in fact, there are more glia than neurons. Because neurons are highly specialized cells that normally do not divide, scientists—including Lei and his team—are exploring ways to convert glial cells into neurons as a potential treatment for neurodegenerative diseases like Alzheimer’s.
In a 2014 study involving members of Lei’s research group, the team tested a method to convert glial cells into neurons by forcing them to express NeuroD1, a transcription factor normally found only in neurons. In injured mouse brains, they observed that astrocytes were successfully converted into functional neurons after expressing NeuroD1. However, as one of the pioneering studies in the field of in vivo neuro-regeneration, this work was controversial. “As with any innovative discovery or technology, it attracted widespread attention and excitement from colleagues in neuroscience and regenerative medicine, while also facing questions and challenges from some peer researchers,” says Lei.
He explains that, in more than a decade since the first publication, researchers from dozens of laboratories worldwide have achieved varying degrees of neuro-regeneration and brain tissue repair using neural transcription factors, including, but not limited to, NeuroD1, or combinations thereof, in various models of central nervous system degenerative diseases and injuries. One of those is Lei’s study testing a NeuroD1-based therapy in a Alzheimer’s disease-like macaque model.
Gene Therapy for Glial-to-Neuron Conversion
Lei and colleagues created the diseased macaque model by overexpressing the human Tau protein in the animals’ hippocampus (a brain region involved in memory, among other functions). After about ten weeks, those hippocampi showed about four times more Tau expression than healthy brains. When counting the number of neurons in some hippocampal regions, detected by the expression of the neuronal marker NeuN, their number decreased by 55-65% in diseased brains compared to healthy ones, which suggests significant hippocampal neuronal loss in the Alzheimer’s-like model.
To treat those monkeys, Lei and the team developed a gene therapy: a treatment that involves delivering genetic material via a carrier into cells to treat a disease. Lei’s gene therapy included the NeuroD1 transcription factor and the GFP protein (to track infected cells under the microscope) delivered via a modified adeno-associated virus (AAV) as the carrier.
After six weeks of AAV-NeuroD1-GFP injection in the brain, macaques’ hippocampi showed NeuroD1 expression (detected by looking at GFP expression) mainly in astrocytes (detected by expression of a transcription factor in these glial cells, GFAP). Thirty weeks later, changes to the expression of NeuN suggested a conversion of NeuroD1-expressing hippocampal astrocytes into neurons. In addition to changes in glial-to-neuronal gene expression profiles, the scientists found that NeuroD1-expressing cells behaved as excitatory neurons, with a small portion being inhibitory, demonstrating neuronal function.
The NeuroD1-based gene therapy also helped in other physiological aspects of Alzheimer’s disease: it decreased inflammation in the brain.
“Based on our transcriptomic analysis and some unpublished data, the mechanisms by which NeuroD1-based gene therapy suppresses neuroinflammation involve altering the state of astrocytes overexpressing the transcription factor [NeuroD1], thereby reducing the number of reactive astrocytes in neuroinflammation,” says Lei. “Additionally, through interglial signaling communication, it improves the state of activated microglia [found in Alzheimer’s brains].”
Another improved physiological aspect that surprised the team was the restoration of the brain-blood barrier, which had been compromised by the disease. “Since the endfeet of astrocytes overexpressing the transcription factor NeuroD1 are an important structural component of the blood–brain barrier, we had initially expected that the blood–brain barrier in the AD-like macaque brain tissue would be compromised [after treatment] to some extent,” says Lei. “However, in fact, the damaged blood–brain barrier in the AD-like model macaque brain was partially repaired by the gene therapy.”
Functional Improvements Beyond Molecular Changes
As one of the major clinical impairments in AD patients, memory loss was evaluated in the animals. Lei and his team used a test called “delayed response” in which monkeys were required to briefly memorize the location of food rewards concealed in one of three covered wells. A monkey was judged to have memorized the food locations if, after a delay with its view blocked, it chose correctly on the first try in at least 26 of 30 trials for three days in a row. The “memory retention interval” is the longest delay during which it could still remember the location. When tested, AD-model monkeys exhibited a substantial decline in their “memory retention interval” after eight weeks of overexpressing Tau but, 21 weeks after treatment with the NeuroD1-based gene therapy, showed a remarkable improvement, approaching pre-Tau intervention levels.
Besides these promising results, several limitations should be considered. First, the AD model used in this work only involved diseased hippocampi, whereas in human patients the pathology affects the entire brain. Second, the number of animals used in this study was low, particularly the number of females, who are most affected by Alzheimer’s in real life. To address this limitation, “in our ongoing and upcoming series of studies on the pathological mechanisms and gene therapy of Alzheimer’s disease, we will increase the proportion of female animals,” says Lei. Third, there is ongoing controversy regarding the extent to which glial-to-neuron conversion truly occurs.
Nonetheless, these findings point to promising future developments. Building on this study, the company NeuExcell Therapeutics has initiated a clinical study in AD patients. According to Lei, NeuExcell was founded by Professor Gong Chen, a co-corresponding author of the study, and the trial is being conducted in collaboration with Professor Jiong Shi’s team at Anhui Provincial Hospital (the First Affiliated Hospital of the University of Science and Technology of China). With a clinical trial now underway, this research represents an important step toward treatments that could slow, stop, or even partially reverse the effects of Alzheimer’s disease, bringing some optimism to patients and their families.
Reference: Z. Jiang et al., A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair in Alzheimer’s Disease-Like Non-Human Primate Model, Advanced Science (2026). DOI: 10.1002/advs.202520239
Featured image adapted from the work of Smanatha Ing via Flickr, under CC BY-SA 2.0
