Alzheimer’s disease represents one of the most prevalent neurodegenerative disorders affecting millions of people worldwide. According to  WHO, currently, more than 55 million people have dementia worldwide, with nearly 10 million new cases every year. Alzheimer’s disease is the most common form of dementia and may contribute to 60–70% of cases.

Unfortunately, there are not many effective therapies available to reverse the course of these illnesses. CRISPR, or the Clustered Regularly Interspaced Short Palindromic Repeats system, is becoming one of the most potent tools in the hunt for novel pharmaceuticals. Among its many applications, CRISPR technology is facilitating the identification of drug targets more quickly, thereby expediting the process of finding new drugs and creating frameworks for the creation of treatments that will be used in the future.

In this article let’s see how the CRISPR-Cas9 systems have been bringing in revolution in the treatment of Alzheimer’s disease.

Genes of Alzheimer‘s: Key Players of Memory Fading

Although the precise causes of the illness are still unknown, scientists think that a mix of environmental, lifestyle, and genetic factors may be responsible. Scientists have also found several gene mutations that cause the disease to be passed on from parent to child.

Research published in PLOS Medicine has identified four main proteins in association with Alzheimer’s, amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2), and apolipoprotein E (APOE). 

The first three have been connected to early-onset (familial) Alzheimer’s disease while the fourth gene mutation is thought to be a significant risk factor for late-onset.

CRISPR in Alzheimer’s: Can it Bring a Change?

Alzheimer’s disease has a significant social and economic impact and is a major global health concern. In addition to excessive glial cell activation, it is characterized by the formation and accumulation of phosphorylated Tau and amyloid-beta 42 (Ab42). Moreover, two crucial aspects of Alzheimer’s are reduced neurotrophin signaling and compromised synaptic function.

Clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins 9 system (CRISPR/Cas9) gene editing is a relatively new and highly significant strategy that has garnered interest due to its potential benefits in the management and treatment of Alzheimer’s disease.

CRISPR-mediated disease modeling studies for Alzheimer’s

There is a large array of genes associated with Alzheimer’s disease and related dementias (ADRD), but the interplay between them is unclear. 

Recently, research published in the journal “Neuron” expressed an NIH initiative known as the Inducible Pluripotent Stem Cell Neurodegeneration Initiative (iNDI). A standardized set of isogenic iPSC lines with more than 100 mutations linked to ADRD was produced by the study. iNDI produced multiple SNVs per gene across multiple targets in induced pluripotent stem cells by using CRISPR editing.

CRISPR to identify new proteins & biomarkers for Alzheimer’s

Researchers from the University of Tokyo used a CRISPR-Cas9 screening technique to identify a protein that identified Alzheimer’s is caused by integrin-binding protein 1 (CIB1) and calcium.

A  group of Spanish researchers noticed that when neurogenesis advanced in the medial frontal gyrus of Alzheimer’s patients, the expression levels of the endoplasmic reticulum protein STIM1 (Stromal Interaction Molecule 1) dropped. By disrupting the STIM1 gene expression in the SH-SY5Y neuroblastoma cell line by using CRISPR-Cas9, they were able to show that a decrease in STIM1 results in a change in the way calcium ions are transported through the plasma membrane of neurons, which ultimately leads to cell death. 

Another team of scientists from Spain observed that STIM1 (Stromal Interaction Molecule 1- an endoplasmic reticulum protein) expression levels decreased in the medial frontal gyrus of Alzheimer’s patients with the progression of neurogenesis. The study published in the Journal of Molecular Medicine used CRISPR-Cas9 to disrupt the expression of the STIM1 gene in the SH-SY5Y neuroblastoma cell line. Using this they were further able to demonstrate that STIM1 deficiency triggers cell death due to changes in the transport of calcium ions through the plasma membrane of neurons.

Identification of this new biomarker will be useful in understanding the role of STIM1 in the pathogenesis of the disease.

CRISPR to correct mutations in presenilin genes

Early-onset familial Alzheimer’s disease has been linked to mutations in the presenilin 2 (PSEN2) gene. In this study, a presenilin 2 mutation in iPSC-derived neurons was corrected using CRISPR.

The basal forebrain cholinergic neurons (BFCNs) are among the first cell types to be affected in Alzheimer’s disease. Impaired short-term memory has been linked to their dysfunction. The scientists used cell lines from PSEN2 mutation carriers and controls to create human BFCNs from iPSCs. The carriers showed an electrophysiological deficit in addition to an increase in Aβ42/40 in BFCNs. The scientists were able to show that the cells’ electrophysiological function and Aβ secretion had returned to normal after using CRISPR-Cas9 to correct the PSEN2 point mutation. 

Another study published in “Stem Cell Research” was able to use CRISPR to correct the PSEN1 mutations in iPSCs.

CRISPR-edited APP gene offering treatment opportunities

Alzheimer’s disease which is dominantly inherited has been linked to the Swedish mutation (APPswe) in the APP gene. In this study, which was published in “Molecular therapy. Nucleic acids,” researchers employed CRISPR to target and interfere with the gene’s mutant allele precisely. Additionally, they were able to demonstrate in vivo and ex vivo that this led to a reduction in pathogenic Aβ. The study’s findings indicate that this might be a useful therapeutic approach in the future.

Another team led by Dr. Takaomi Saido has identified protective mutations in the 3’ UTR of the APP gene in mice. They then used CRISPR to replace the wild-type APP gene with the mutated versions to induce a rodent version of Alzheimer’s disease. The results of their research showed that the mice with mutated forms of the APP gene were protected against cognitive decline and displayed lower levels of accumulated amyloid plaques.

Summing it up

The use of CRISPR-Cas9 in Alzheimer’s disease research is still in its early stages. While it may still be too early to use CRISPR as a therapeutic tool, it can undoubtedly be a vital tool for researchers studying the pathophysiology of Alzheimer’s disease. It’s critical to comprehend the underlying disruption in processes that contribute to the disease to find a treatment. CRISPR is the ideal tool for disrupting genes, and it can help researchers determine how a specific gene may contribute to the development of a disease.

Off-target effects are one of the challenges CRISPR must overcome before it is suitable for use as a therapeutic tool. With genome editing and precision medicine, AI can enable personalized medicine based on genetic profiles. AI looks at a patient’s genetic data to identify changes, variants, and biomarkers associated with different diseases.

Codewave EIT’s AI solutions insightfully enable the diagnosis of complex problems, prediction of possible solutions with probability of success, and discovery of potential new drugs.

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To understand the impact of innovative technologies in CRISPR-mediated solutions, you can talk to our team. We are here to give innovative solutions to Mental Healthcare.