Alzheimer's Research

As we embark on the journey of life, our minds serve as the compass guiding us through a myriad of experiences and memories. However, with the passing of time, the aging process can cast a shadow on this cognitive prowess. Cognitive decline, a natural part of growing older, has long been a concern for individuals seeking to maintain mental acuity and preserve their quality of life.

Fortunately, as scientific research advances, new avenues of exploration emerge, shedding light on potential solutions to combat cognitive decline. One such area of intrigue involves the use of peptides, which hold promise as a fascinating tool in the fight against aging-related cognitive impairment.

In this blog post, we will delve into the relationship between peptides and cognitive decline during the aging process. We will explore the underlying mechanisms behind cognitive decline, examine the role of peptides in maintaining cognitive function, and delve into recent scientific findings that offer hope for restoring and preserving cognitive abilities as we age.

Cognitive Decline
Cognitive decline is a common phenomenon associated with aging, with its prevalence increasing as individuals grow older. Alzheimer’s disease, the most common cause of dementia, affects a significant number of people worldwide. In the United States, an estimated 6.2 million individuals aged 65 and older were living with Alzheimer’s dementia in 2021. Globally, it was estimated that around 50 million people had dementia in 2020, with Alzheimer’s disease accounting for most cases. Mild Cognitive Impairment (MCI), which represents a stage between normal aging and dementia, affects approximately 10-20% of individuals aged 65 and older. Age-related cognitive decline, a milder form of cognitive impairment associated with aging, is experienced by a significant proportion of older adults. The exact prevalence of age-related cognitive decline is challenging to determine due to variations in diagnostic criteria. However, it is understood that a substantial number of older individuals will experience some degree of cognitive decline.

The PLGA-based curcumin treatment for AD uses nanoparticles to transport curcumin to the brain. ^[1-3] The nanoparticles comprise PLGA, a biocompatible and biodegradable polymer.^[5] The nanoparticles are small enough to cross the BBB, which is typically challenging for medications targeting the brain.^[5] Once the nanoparticles reach the brain, they release curcumin, reducing neuroinflammation, inhibiting the aggregation of misfolding proteins, and improving neuroprotection and cognition.^[1-5] In other words, by decreasing neuroinflammation and inhibiting the development of abnormal proteins, PLGA-based curcumin remedy can slow down or even reverse the advancement of AD.^[5-9 Several articles have shown that the PLGA-based curcumin treatment can help in combating other neurodegenerative disorders like Parkinson’s disease (PD) by reducing PD symptoms, apoptosis, and oxidative stress.^[12] The PLGA-based curcumin therapy could provide a wide range of benefits in AD patients by decreasing the progression of most of the pathological aspects of the disorder.^[5-10] In addition, this therapy overcomes one of the most challenging aspects of AD treatment, which is to cross the BBB.^[1] PLGA-based curcumin provides a safe, viable, stable, nontoxic, and efficient way to fight AD progression.^[11] Clinical trials for PLGA-based curcumin are ongoing, aiming to study the effectiveness and safety of using this treatment on humans.^[10-13] Even though the results are unavailable, the preclinical studies show remarkable results in mice models.^[12]

Benefit summary of the nano-based curcumin delivery system (PLGA-based curcumin)

• Decrease Amyloid beta and tau misfolding, accumulation, and toxicity.
• Improves memory and cognition in AD models (see Fig. 2).
• High circulation time in blood and bioavailability
• Cross the Blood-brain barrier
• Decreases neuronal cell death.
• Reduces neuroinflammation dramatically.
• Enhances neuroprotection and neuroplasticity.
• Inhibit the activation of cytokines.
• Promotes the heat shock response.
• Reduces the immune cell infiltration.

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]