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Lipid Nanoparticles Deliver RNA to the Brain for Alzheimer’s
The inhibition of PU.1 using RNA therapy delivered with lipid nanoparticles as a novel treatment for Alzheimer’s disease.
Neurodegenerative disorders are typically linked to chronic neuroinflammation. Alzheimer’s disease (AD) is not an exception since chronic inflammation is one of the hallmarks that contributes to the progression of the disorder.[2] Microglia cells are the main characters in promoting neuroinflammation since they are the most abundant brain immune cells. [2-5] Microglia cells are well known to clear different waste materials from the brain and confer neuroprotection (see Fig.1).[6] However, recent studies have pointed to the presence of AD-risk locus in the microglia genome.[2] AD-risk loci are specific fragments located in the genome that can potentially promote AD development.[3,14] These AD-risk loci open many opportunities for RNA therapeutic methods.[3,6] RNA therapies have been studied for almost all types of disorders, like Parkinson’s disease, AD, and cancer, among others.[3,9,10] The problem with this type of therapy is that it is difficult to find the correct method for transfection, depending on the area or interest. The transfection process, which introduces RNA into cells, is used to modify the host cell genome, changing the cell fate. [10,11] In the case of inhibiting with RNA transfection therapy, the siRNA is used. [2,12] siRNA (small interfering RNA) are small fragments of artificially synthesized RNA capable of inhibiting a specific genome fragment.[10]Figure 1. Show the roles of the microglia in a healthy brain versus one with Alzheimer’s disease.[6]
Amylin Protein Targets Alzheimer’s disease
The remarkable benefits of amylin protein as a treatment for Alzheimer’s disease
Alzheimer’s disease (AD) is known to be a multifactorial disease. [2] That is, several factors contribute to the pathogenic development of this disorder. However, amyloid beta (Aβ) accumulation in the brain is highlighted as critical in developing the disease. [2,3] Recent studies have shown that long before the onset of symptoms of the disease, the accumulation of the Aβ protein forms plaques between neurons which turn out to be very toxic to neurons. [2,3] In addition, it has been exposed that these plaques are responsible for progressive cognitive impairment. [1,2,3] The accumulation of Aβ induces neuronal cells to die. Aβ plaques constantly induce neuroinflammation, so it, in turn, causes injury to nerve cells affecting memory and other cognitive factors. [2,3]
Representation of the hallmarks of AD in the brain.
Countless studies have found a protein with Aβ like characteristics called amylin. [1,2,3,5] These two proteins generate soluble forms of oligomeric form intermediates, which have been found to have potent cytotoxicity. [2,6] This cytotoxicity affects cell membranes and organelles, inducing inflammatory responses, causing reactive oxygen species, and overloading the protein-splitting. [1,2] These two proteins are so similar that their oligomers can even interact with each other accumulating in the brain in the same way as Aβ alone. [1,2] Amylin accumulation in the brain of AD rat models has been found to contribute significantly to brain damage caused by the illness. [2,6]In addition to AD, amylin has been found in high concentrations in the brain of patients with dementia and type 2 diabetes(T2DM). [2]
The Role of Cell-Permeable Peptides and The JNK Family in Preventing Neuronal Degeneration
Figure 1:Â Â Â Â Neuroprotective features of CPPs in combination with other molecules or peptides for treating PD and AD.
JNK family participates in the apoptosis pathway, also known as programmed cell death.[4] The apoptosis mechanism is used to eliminate cells that are damaged in anyway. This mechanism is suitable for healthy people because it helps avoid developing cancer and other disorders.[1] On the other hand, apoptosis is detrimental in neurodegenerative diseases that share the abnormal accumulation of misfolded proteins, contributing to dementia, cognitive loss, memory loss, behavioral problems, and sleep problems, among others, through neuronal cell loss.[3,5,7] In addition, the JNK family also participates in pathways related to regulation, plasticity, development of the Central Nervous System (CNS), inflammation, and autophagy.[9] The well-functioning of all these processes is vital. Recent studies suggested that an imbalance of the JNK family members can accelerate the progression of both AD and PD pathologies. One of the hallmarks of AD is the aggregation of amyloid beta (Aβ) in the extracellular area.[7] The overexpression of Aβ triggers the activation of JNK-3, which also participates in the formation of Aβ42, a toxic species that affects the neuron’s cell function when it accumulates.[7] It is unclear whether the neurodegenerative disorder or the JNK imbalance comes first. However, they both have a direct relationship where PD and AD patients show high levels of JNK in the brain (postmortem), and irregular levels of the JNK family accelerate the progression of both disorders (see Fig. 2). [5,9] JNK imbalance could also lead to increased inflammation responses, low plasticity, and a flaw in autophagy performance, among other related adverse effects. An increase in apoptosis in PD and AD patients causes a decrease in neurons in the brain, affecting cognitive, behavioral, and memory performance.[8] JNK also decreases the α-syn accumulation in PD models, contributing to neuroprotection.[10] JNK pathway influence positively many vital processes of the body unless an imbalance occurs. [2,8] JNK has been the target for treating several diseases like cancer, strokes, PD, AD, Huntington’s disease, and other neurodegenerative disorders, showing promising results. More investigations need to be done to comprehend better how the correct levels of JNK can help combat important hallmarks of degenerative illnesses to eventually prevent or revert the progression of related diseases like PD and AD. In general, the benefits of inhibiting JNKs for treating neurodegenerative disorders are:
ÂImproving autophagy for the elimination of misfolded proteins (Aβ (AD), tau protein (AD), and α-syn (PD)
Increasing cell proliferation.
ÂDecreasing programmed cell death.Â
Reducing brain damage.
Decreasing cognitive decline.
Increasing gene expression.
Decreasing neuroinflammation responses
Improving memory
Providing neuroprotection
Improving synaptic connections
PEPITEM Research: Osteoporosis and Bone Strength
PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration)
PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) was first identified in 2015 by researchers at the University of Birmingham. New research published in Cell Reports Medicine demonstrates for the first time that PEPITEM could be utilized as a novel early clinical intervention to mitigate the effects of age-related musculoskeletal diseases. The data indicates that PEPITEM enhances bone mineralization, formation, and strength, effectively reversing bone loss in animal models.
This research was supported by significant grants from the Medical Research Council and the Lorna and Yuti Chernajovsky Biomedical Research Foundation, which invests in research for developing new targeted medicines to improve health outcomes. Additional funding was provided by the British Society for Research on Ageing and Versus Arthritis.
Bone undergoes constant formation, reformation, and remodeling throughout life, with up to 10% of human bone being replaced annually. This process involves a complex interplay between osteoblasts, which form bone, and osteoclasts, which break down bone. Disruptions to this finely tuned process are responsible for diseases such as osteoporosis and rheumatoid arthritis, characterized by excessive bone breakdown, or ankylosing spondylitis, marked by abnormal bone growth.
PEPITEM’s ability to enhance bone formation without adversely affecting osteoclast activity presents a promising therapeutic strategy. By promoting osteoblast activity and reducing osteoclast numbers via specific signaling pathways, PEPITEM has shown potential in increasing bone density and strength, suggesting its effectiveness as an early intervention for age-related bone diseases. This advancement could offer a new approach to maintaining bone health and preventing fractures, addressing a significant need in the treatment of osteoporosis and other musculoskeletal disorders.
Current osteoporosis therapies, such as bisphosphonates, primarily target osteoclasts to prevent further bone loss. While there are new anabolic agents available that promote new bone formation, their clinical use is limited. For example, teriparatide (parathyroid hormone, or PTH) is effective for only 24 months, and romosozumab (an anti-sclerostin antibody) has been linked to cardiovascular events. These limitations show the urgent need for developing new therapies to stimulate bone repair, especially in age-related musculoskeletal diseases like osteoporosis.
To address this need, a team of researchers led by Dr. Helen McGettrick and Dr. Amy Naylor, along with Dr. Jonathan Lewis and Ms. Kathryn Frost from the Institute of Inflammation and Ageing at the University of Birmingham, and Dr. James Edwards from the Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences at the University of Oxford, have been investigating the therapeutic potential of PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) in these conditions. Their research aims to explore whether PEPITEM can effectively stimulate bone repair and provide a new therapeutic avenue for treating osteoporosis and other age-related musculoskeletal disorders. By enhancing bone mineralization, formation, and strength, PEPITEM offers an exciting alternative that could overcome the limitations of existing therapies and significantly improve patient outcomes.
Peptides for Bone Healing Research
Our bones are the foundation of our bodies, protecting vital organs like the brain and heart while providing a solid structure against which muscles can work. They are also responsible for producing most of our red blood cells and play a critical role in the immune system. Bone problems are becoming more prevalent, however, and this has led researchers to investigate potential means of mitigating these problems. Peptides have emerged as one of the forerunners in the fight to preserve bone health with peptides like ipamorelin, transforming-growth factor-beta, bone morphogenic proteins, and others showing a great deal of promise.
Increasing Prevalence of Bone Problems
Despite the common perception of bones as static, and unchanging structures, research has shown them to be exceptionally dynamic. Bone isn’t simply deposited as we grow and then stops, but rather is in a constant state of flux. The balance between bone growth and bone breakdown is necessary to maintain blood calcium levels, allow bones to respond to changes in stressors, promote bone healing following injury, and much more. As it turns out, diseases that affect bone are actually diseases that alter this careful balance and thus treating them is more complex than simply encouraging bones to grow.
Bone deterioration and disease are becoming more and more commonplace for several reasons. First, as the population ages the incidence of bone-related diseases like osteoporosis is increasing as well[1]. Aging is the single greatest risk factor for bone loss, but it isn’t the only contributor to the problem. Other reasons for increased bone disease include vitamin D deficiency, increased prevalence of diseases that impact bone health, increasing use of medications that degrade bone health, nutritional issues, and increasingly sedentary lifestyles.
Of course, bone loss and degradation are not the only problems to confront our skeletal system. Fractures that result from trauma are also a major cause of lost time at work as well as lost quality time. Many fractures take eight to twelve weeks to heal, so anything that can be done to speed up this recovery process would help to drive down both societal and medical costs.
