This study investigated the use of extracellular vesicles (EVs) derived from induced stem cells (hiPSC-NSCs) to treat Alzheimer’s disease (AD). EVs carry anti-inflammatory proteins and miRNAs that, when applied via nasal spray, reduce inflammation, beta-amyloid plaques, and tau tangles in AD mice. They also improved cognition and mood, offering a potentially safe and effective therapy to slow disease progression without the risks associated with stem cells.
Alzheimer’s disease (AD) is characterized by severe changes in the brain that cause memory loss, cognitive difficulties, and mood changes.
These changes cause chronic neuroinflammation, which is an ongoing inflammatory response in the brain.
There is also a buildup of beta-amyloid-42 (Aβ42) plaques, which are protein deposits that form between brain cells, along with neurofibrillary tangles within the cells, formed by a protein called tau, which when damaged become tangled and impair cell function.
All together, they cause the loss of synapses, that is, the connections between brain cells begin to deteriorate, and neurodegeneration, which is the progressive death of brain cells.
These changes contribute to the progression of the disease. Current therapies, however, are not effective in slowing the progression of AD, which is why new approaches to treating the disease are being sought, especially those that can help maintain cognitive function and well-being longer after diagnosis.
Transplants of neural stem cells (NSCs), which are cells that have the potential to develop into different types of brain cells, have shown a potential to improve brain function in models of several neurological diseases.
However, using these cells in humans poses safety risks, such as the possibility of them multiplying uncontrollably. Furthermore, in the case of AD, which affects multiple regions of the brain, it is particularly difficult to ensure that the transplanted cells integrate as needed in all of these areas.
Neural stem cells (NSCs) in culture
To overcome these challenges, scientists are studying the secretome of NSCs, which are substances produced and released by these cells, including extracellular vesicles (EVs).
EVs are small particles released by stem cells that carry genetic components and proteins, allowing the cells to communicate with and influence the behavior of recipient cells.
EVs derived from NSCs have the advantage of carrying therapeutic molecules without the risks associated with stem cells because:
They do not replicate: This avoids the risk of tumor formation.
They cross the blood-brain barrier: This is a protective structure in the brain that prevents the entry of various substances, but EVs can easily pass through it.
They can be administered non-invasively, for example, through an intranasal spray (through the nose), making them a practical and quick option.
These EVs, derived from laboratory-derived induced pluripotent stem cells (hiPSC-NSC-EVs), carry miRNAs and anti-inflammatory proteins that may help reduce neuroinflammation in the brain.
In the study, researchers at Texas A&M University used mice genetically engineered to develop AD and administered EVs via nasal spray to young mice still in the early stages of the disease.
5xFAD transgenic mouse was used in the study.
This was done to assess whether EVs could reduce the excessive activation of brain cells called microglia and astrocytes, which normally contribute to neuroinflammation. Also, decrease the accumulation of beta-amyloid plaques and tau tangles. Or even improve the cognitive function and mood of the mice.
They found that EVs were taken up by microglia and astrocytes and modified the genetic activity of these cells, reducing signs of inflammation.
The microglia maintained their normal "cleaning" function in the brain, with no changes in their ability to phagocytize (ingest harmful particles).
After administration of EVs, there was a reduction in neuroinflammation. EVs decreased the activity of genes linked to inflammation in both microglia and astrocytes.
When analyzing the beta-amyloid plaques, they found a lower accumulation, in addition to fewer tau tangles. This suggests that EVs may help slow the accumulation of these toxic substances, which harm brain cells in AD.
Intranasal administration of extracellular vesicles of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) to 5xFAD mice reduced amyloid plaques and phosphorylated tau. Figures (A-B) illustrate the distribution of amyloid plaques in the hippocampus of 5xFAD mice receiving vehicle (Veh, A) or hiPSC-NSC-EVs (B). Bar graphs compare the area fraction (AF) of amyloid plaques (C, D), soluble Aβ42 concentration (E, F), and p-tau (G, H) in males (C, E, G) and females (D, F, H) between the AD-Veh and AD-EVs groups.
Finally, they found an improvement in cognitive function and mood. Mice receiving treatment showed improved performances in memory and behavior tests.
These findings indicate that EVs from stem cells could act as a cell-free therapy for AD, offering a safe and potentially effective alternative to treat the disease, with the potential to maintain cognitive function for longer and reduce the inflammatory damage associated with Alzheimer's.
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Extracellular vesicles from human-induced pluripotent stem cell-derived neural stem cells alleviate proinflammatory cascades within disease-associated microglia in Alzheimer's disease
Leelavathi N. Madhu, Maheedhar Kodali, Raghavendra Upadhya, Shama Rao, Yogish Somayaji, Sahithi Attaluri, Bing Shuai, Maha Kirmani, Shreyan Gupta, Nathaniel Maness, Xiaolan Rao, James J. Cai, Ashok K. Shetty
Journal of extracellular vesicles. Volume 13, Issue 11. November 2024 e12519
Abstract:
As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice. IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocyte soma and processes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-inflammasome and interferon-1 (IFN-1) signalling displayed reduced expression in microglia. Adding hiPSC-NSC-EVs to cultured human microglia challenged with amyloid-beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen-activated protein kinase and IFN-1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function. Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.
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