Summary: Researchers at Texas A&M report a promising intranasal therapy that targets chronic neuroinflammation in early-stage Alzheimer’s disease. Using extracellular vesicles derived from neural stem cells, the nasal spray reduced inflammatory signaling and the accumulation of Alzheimer’s-related proteins and plaques in an animal model, suggesting potential to slow disease progression by many years.
The therapy works by altering microglia, the brain’s resident immune cells, to curb damaging inflammatory responses while preserving their ability to clear toxic protein deposits. If translated successfully to humans, this approach could meaningfully improve quality of life and delay severe cognitive decline after diagnosis.
Key Facts:
- Targeted delivery: An intranasal spray delivers neural stem cell-derived extracellular vesicles to the brain, where they reach microglia and astrocytes.
- Microglial modulation: Treatment shifts microglial gene expression to reduce proinflammatory cascades while maintaining phagocytosis of amyloid plaques.
- Potential impact: The researchers estimate the intervention could delay Alzheimer’s progression by roughly 10–15 years if replicated in humans, improving long-term cognitive outcomes.
Source: Texas A&M University College of Medicine
New intranasal therapy may slow Alzheimer’s progression
A study published in the Journal of Extracellular Vesicles describes an experimental nasal-spray therapy that delivers extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)–derived neural stem cells (NSCs). In early-stage Alzheimer’s animal models, intranasal administration of these EVs reduced harmful neuroinflammatory signaling and diminished hallmark pathological features such as amyloid-beta plaques and phosphorylated tau.
The research team, led by Ashok K. Shetty, Ph.D., a University Distinguished Professor and associate director at the Institute for Regenerative Medicine, and collaborator Madhu LN, Ph.D., administered the EV-containing nasal spray to young, 3-month-old 5xFAD mice, a widely used model of early Alzheimer’s pathology. The intranasally delivered EVs entered the brain, were taken up by microglia— including those closely associated with amyloid plaques— and also interacted with astrocytes.
Single-cell RNA sequencing showed that EV-treated microglia and astrocytes displayed transcriptomic shifts consistent with reduced activation. Genes associated with disease-associated microglia, the NLRP3 inflammasome, and interferon-1 signaling were downregulated in microglia. Astrocytes likewise showed decreased expression of genes linked to interferon-1 and interleukin-6 signaling. Importantly, these molecular changes persisted for at least two months after treatment and did not impair microglial phagocytic function.
In parallel laboratory experiments, adding hiPSC-NSC-EVs to cultured human microglia challenged with amyloid-beta oligomers produced similar anti-inflammatory effects, supporting the observation that the EV cargo can directly modulate microglial responses to Alzheimer’s-related insults.
These combined molecular and functional outcomes correlated with reductions in microglial clusters, inflammasome components and their downstream mediators, as well as a decrease in astrocyte hypertrophy, amyloid-beta plaque burden, and phosphorylated tau in the hippocampus. Behaviorally, treated animals showed improvements in cognitive and mood-related measures, indicating that early EV intervention preserved aspects of brain function.
Shetty and colleagues have filed a patent on the intranasal use of neural stem cell-derived EVs for Alzheimer’s and other neurological conditions. Funded by the National Institute on Aging, the laboratory’s work is continuing, and the team hopes follow-up studies will advance this approach toward clinical testing. They estimate that, if validated in people, early application of this therapy could delay the onset of severe Alzheimer’s-related cognitive decline by an estimated 10 to 15 years after diagnosis.
“This therapy shows promise because the molecular cargo within these extracellular vesicles appears to limit the harmful neuroinflammatory cascades that drive neuronal damage, while preserving microglial clearance functions,” Shetty says. The researchers emphasize that their findings represent an early but important step toward a potential disease-modifying treatment that targets inflammation rather than only addressing symptoms.
About this Alzheimer’s disease research news
Author: Laura Tolentino
Source: Texas A&M University College of Medicine
Contact: Laura Tolentino – Texas A&M
Image: The image is credited to Neuroscience News
Original Research: Open access. “Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer’s disease” by Ashok K. Shetty et al., Journal of Extracellular Vesicles.
Abstract
Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer’s disease
Current treatments for Alzheimer’s disease (AD) largely fail to alter disease trajectory, so interventions that can restrain progression and preserve brain function are urgently needed. Anti-inflammatory extracellular vesicles derived from hiPSC-NSCs represent a potential disease-modifying biologic therapy for AD.
This study examined the effects of intranasal administration of hiPSC-NSC-EVs in 3-month-old 5xFAD mice. Following treatment, EVs incorporated into microglia—including plaque-associated microglia—and contacted astrocyte somas and processes in the brain. Single-cell RNA sequencing revealed transcriptomic signatures consistent with reduced activation of microglia and astrocytes.
Multiple genes linked to disease-associated microglia, NLRP3 inflammasome activation, and interferon-1 signaling showed reduced expression in microglia. Adding hiPSC-NSC-EVs to cultured human microglia exposed to amyloid-beta oligomers induced comparable transcriptional changes. Astrocytes displayed lowered expression of genes related to interferon-1 and interleukin-6 signaling.
The modulatory effects of hiPSC-NSC-EVs on hippocampal microglia persisted for at least two months after treatment and did not impair phagocytosis. These effects included reductions in microglial clusters and inflammasome complexes, lower concentrations of inflammasome mediators and end products, attenuated activation of p38/MAPK and interferon-1 signaling pathways, and unchanged phagocytic function.
Treated animals also exhibited decreases in astrocyte hypertrophy, amyloid-beta plaques, and phosphorylated tau in the hippocampus, accompanied by improved cognitive and mood-related behaviors. These findings demonstrate that early hiPSC-NSC-EV intervention can maintain better brain function in an AD model by dampening harmful neuroinflammatory signaling cascades and reducing key pathological markers.
This work provides the first demonstration that hiPSC-NSC-EVs can induce beneficial transcriptomic changes in activated microglia and reactive astrocytes, thereby restraining neuroinflammatory cascades in an Alzheimer’s disease model.