Alzheimer's Research

Mechanism of the V24P (10-40) scavenger peptide.

Figure 1.

Several studies show that V24P (10-40) PEI decreases the accumulation and toxicity of both Aβ40 and Aβ42 in the hippocampus and the cortex of AD mice models (see Fig.2).^[3,5] V24P (10-40) PEI peptide also significantly decreases the amyloid-β plaque aggregation in AD mice models.^[7] It is well known that amyloid-β plaques and neurofibrillary tangles tend to accumulate in the olfactory bulb, damaging olfaction in the early stages of AD. ^[3] This novel peptide demonstrated that it could reduce both plaques and neurofibrillary tangles in the olfactory bulb.^[3,6] For this reason, the V24P (10-40) PEI peptide is an excellent candidate for preventing the pathogenesis of AD from its early stages.^[1-4]After testing different quantities (mg) of V24P (10-40) PEI, the investigators found that administering 1.6mg 6 times a week for eight months can reduce the amyloid-β in the hippocampus by 81%.^[3] When comparing those results with other peptides made specially for decreasing the amyloid-β in the hippocampus, V24P (10-40) PEI shows the best performance (see Table 1).^[3] Several studies suggest that V24P (10-40) PEI has excellent potential in slowing down the pathogenesis of AD by trapping and eliminating the overexpressed amyloid-β peptides in the olfactory bulb, hippocampus, brain cortex, and other possible areas.^[2-4] AD is known to be a multifactorial disorder. However, a large percentage of patients show amyloid-β aggregation postmortem.^[5] V24P (10-40) PEI is one of the few peptides tested in vivo, showing excellent results in decreasing self-aggregate proteins in the brain. ^[3,6] Stabilizing the amyloid-β levels in the brain can reduce neuronal cell mortality and memory loss, decreasing the chances of developing AD. ^[2] 

Results of the Aβ40 and Aβ42 levels in the (a) hippocampus and (b) the cortex after the administration of V24P (10-40) PEI peptide

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]

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]

Figure 1:     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:

­Improving autophagy for the elimination of misfolded proteins (Aβ (AD), tau protein (AD), and α-syn (PD)

• Increasing cell proliferation.
• ­Decreasing programmed cell death.­
• Reducing brain damage.
• Decreasing cognitive decline.
• Increasing gene expression.
• Decreasing neuroinflammation responses
• Improving memory
• Providing neuroprotection
• Improving synaptic connections