Exploring the Connection between CRISPR‑Cas9 and Alzheimer's

Disease Therapy

Xinyu Lin

Chengdu Experimental Foreign Languages School, Chengdu, China

Keywords: CRISPR‑Cas9, Alzheimer's Disease, Gene Therapy.

Abstract: Alzheimer's disease (AD), which is a neurodegenerative disorder, has a pathophysiology that remains unclear,

and there is a lack of effective treatments for this condition. The CRISPR/Cas9 gene - editing technique shows

great promise in treating AD. It can target genes like APP, BACE1, and APOE to reduce Aβ production.

However, its clinical application faces challenges. Delivery methods, including biological systems, local

injections, and viral/non - viral vectors, have limitations such as poor blood - brain barrier penetration,

invasiveness, and immunogenicity. Animal models created by CRISPR/Cas9 are beneficial for researching

the pathogenesis of AD. However, issues such as off - target effects, long - term safety, and ethical concerns

still need to be resolved. In upcoming research, it is essential to focus on improving delivery systems and gene

- editing approaches. Only in this way can the potential of CRISPR/Cas9 in the treatment of AD be fully

realized.

1 INTRODUCTION

Alzheimer's disease (AD), a condition of progressive

neurodegeneration, has become a prominent global

health matter. It places a heavy strain not only on

patients and their families but also on healthcare

systems around the world. Even with substantial

research undertakings, the essential

pathophysiology of AD remains only partially

known, and there continues to be a lack of effective

therapeutic tactics. The identification of amyloid-β

(Aβ) metabolism abnormalities as a common

denominator in AD patients—despite the relatively

low prevalence of genetic mutations (about 1 in 100

patients)—has spurred the exploration of novel

therapeutic approaches. Among them, the

CRISPR/Cas9 gene - editing technology has

demonstrated remarkable potential as a possible

treatment method for curbing excessive Aβ

production. CRISPR/Cas9, an adaptive immune

system derived from bacteria and archaea, has

revolutionized the field of gene editing. This

system, which is composed of the Cas9 protein and

a single-guide RNA (sgRNA), has the ability to

precisely recognize and cleave target DNA

sequences. The single-guide RNA (sgRNA) directs

the Cas9 protein to the specific DNA site based on

the base-pairing rules. The Cas9 protein, possessing

various domains including REC I, REC II, the

bridge helix, the PAM-interacting domain, HNH,

and RuvC, induces a double-strand break in the

DNA. The protospacer-adjacent motif (PAM)

sequence is of crucial importance in allowing the

Cas9 protein to identify the target DNA. When

compared to other gene-editing technologies such

as zinc-finger nucleases (ZFNs), transcription

activator-like effector nucleases (TALENs), and

meganucleases, CRISPR/Cas9 offers advantages

such as its simplicity of operation, high efficiency,

and low cost. These attributes have led to their rapid

adoption in various research fields, including AD

research.

In the context of AD treatment, several

promising directions have been explored. Among

the strategies being studied are making edits to the

amyloid precursor protein (APP) gene, reducing the

expression of the β-secretase 1 (BACE1) gene, and

altering the apolipoprotein E ε4 (APOE ε4) gene.

These approaches aim to directly target the

molecular pathways involved in Aβ production and

processing, potentially halting or reversing the

progression of AD. However, translating

CRISPR/Cas9 technology from bench to bedside

for AD treatment is not without challenges. One of

the major hurdles lies in the delivery of the

Lin, X.

Exploring the Connection between CRISPR-Cas9 and Alzheimer’s Disease Therapy.

DOI: 10.5220/0014487000004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 295-300

ISBN: 978-989-758-789-4

295

CRISPR/Cas9 components. While delivery via

biological systems is feasible, it suffers from issues

such as instability, low targeting efficiency, and

poor blood-brain barrier (BBB) penetration. Local

organ injection, such as direct injection into the

brain, can enhance therapeutic efficacy but is highly

invasive, limiting its widespread application.

Delivery through the nasal cavity can bypass the

BBB, yet its effectiveness and potential drawbacks

require further clinical investigation. To better

understand the pathophysiology of AD and evaluate

the efficacy of CRISPR/Cas9-based therapies,

animal models have been developed using this

gene-editing technology. For example, specific

mutations like F681Y, G676R, and R684H have

been introduced into the APP gene of mice and rats,

creating humanized animal models. These models

have provided valuable tools for studying APP

processing and uncovering new disease

mechanisms of AD. This review article aims to

comprehensively summarize the existing

knowledge regarding the application of

CRISPR/Cas9 in the treatment of Alzheimer's

disease (AD). By critically evaluating the existing

literature. The progress made in gene-editing

strategies, the challenges associated with delivery

methods, and the insights gained from animal

models will be discussed. The objective is to offer

an all - encompassing view of the field, recognize

knowledge voids, and provide guidelines for future

research, with the ultimate contribution being to the

advancement of efficacious CRISPR/Cas9 -

centered therapies for AD.

2 THE APPLICATION OF

CRISPR/CAS9 IN THE

TREATMENT OF AD

Despite the fact that surveys suggest that, out of every

hundred Alzheimer's disease (AD) patients, only one

usually has a genetic mutation as the underlying cause

of the disease, abnormalities in Aβ metabolism are

truly a problem that all patients will face.

CRISPR/Cas9 can indeed serve as a potential

treatment method for correcting the overproduction

of Aβ. The main treatment directions currently

understood include the following.

Editing of APP gene: Mutations in the APP

gene can lead to an increase in Aβ production,

which is one of the important causes of AD onset.

Studies have found that knocking out the APP allele

using CRISPR/Cas9 technology can reduce Aβ

protein expression. In a particular study, the

hippocampus of an AD mouse model (Tg2576

mice) was injected with a viral vector that carried

the sgRNA targeting the KM670/671NL mutation

(APPsw) along with the Cas9 enzyme. Following

the injection, after a period of one month, DNA

sequencing results indicated that there was roughly

a 2% insertion/deletion (InDels) in the APPsw

allele. This discovery implies that the

CRISPR/Cas9 system is capable of modifying the

APP gene, thereby offering a possible method for

the treatment of AD that is induced by APP

mutations (Cao et al. 2021). Moreover, in numerous

other studies, the CRISPR/Cas9 technology has

been utilized to selectively modify the C-terminal

part of the APP gene in both cellular and animal

models. Through this editing, the interaction

between APP and BACE1 has been inhibited,

leading to a decrease in Aβ production. At the same

time, it has promoted the neuroprotective APP-α

cleavage process, thereby creating novel paths for

the treatment of Alzheimer's disease (Zhang et al.

2022).

Inhibition of BACE1 Gene Expression: The

Aβ protein is generated through the successive

modification of APP by BACE1 and γ-secretase.

This mechanism makes targeting BACE1 a feasible

approach for treating AD. As illustrated in the

research by Park et al., they formulated a

nanocomplex composed of the R7L10 peptide and

the Cas9-sgRNA ribonucleoprotein complex. This

nanocomplex was then directly injected into the

hippocampus of 5xFAD and App knock-in AD

transgenic mice. As a result, the expression of

BACE1 was successfully lowered, the production

of Aβ was diminished, and the cognitive

impairment in 5xFAD transgenic Alzheimer's

disease (AD) mice was alleviated (Wang et al.

2020). This study indicates that using

CRISPR/Cas9 technology to inhibit BACE1 gene

expression holds promise as an effective method for

treating AD.

Editing of the APOE ε4 gene: APOE4

represents the most potent genetic risk factor for

sporadic Alzheimer's disease. Research findings

have indicated that when CRISPR/Cas9 technology

is employed to convert APOE4 into APOE3, it is

capable of reducing tau phosphorylation levels,

diminishing the accumulation of Aβ, and alleviating

the pathological manifestations associated with

Alzheimer's disease. For example, Wadhwani and

his research team utilized the CRISPR/Cas9 system

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to change the E4 allele existing in induced

pluripotent stem cells (iPSCs) that were derived

from two patients with AD into the E3/E3 genotype.

They discovered that neurons with the E3 genotype

demonstrated enhanced resistance to the cytotoxic

effects induced by ionomycin and displayed

decreased levels of tau phosphorylation (Li et al.

2021). This provides an important basis for gene

therapy targeting APOE4, demonstrating the

potential of CRISPR/Cas9 technology in improving

genetic risk for AD.

3 THE CHALLENGES IN

DELIVERY CHANNELS

The CRISPR/Cas9 technology also faces certain

challenges in delivery methods, with the main

delivery methods and the challenges they face

including the following points.

Drug delivery through biological systems:

Although this approach is workable, it is plagued by

problems such as a lack of adequate stability, low

targeting precision, and difficulties in penetrating

the blood-brain barrier (BBB). For instance,

nanocomplexes are formed by bringing together

positively charged CRISPR/Cas9 peptides and

negatively charged nucleic acid payloads. They

possess a beneficial traits of low immunogenicity

and the capacity to bind to ligands, which enables

their application in a wide range of scenarios.

Nevertheless, when these nanocomplexes are

systemically administered, they encounter

substantial hurdles in efficiently crossing the BBB.

Moreover, the reticuloendothelial system (RES)

will vigorously eliminate them from the

bloodstream (Hu et al. 2020).

Local drug injection into the organ: For

instance, intracerebral injection, while enhancing

the effect of drug action, also possesses a strong

invasiveness, making widespread application quite

challenging. Direct intracerebral injection requires

invasive procedures, which may increase the risk of

infection and has strict limitations on the volume

and frequency of injections, making it unsuitable

for repeated dosing. Administration of drugs

through nasal ducts: This method can effectively

avoid the issue of BBB permeability, but the

specific effects and whether there are other

disadvantages still lack further clinical research.

Current research suggests that nasal drug delivery

could be a promising non - invasive method of

administration. However, additional clinical

investigations are required to establish its safety

and effectiveness. Moreover, it is necessary to

identify any potential problems that might be

associated with this delivery route.

In addition to the aforementioned common

delivery methods, there are other delivery options

available. Regarding viral vector delivery, which

encompasses adeno - associated virus (AAV),

adenovirus (AdV), lentivirus (LV), and others.

Among these, adeno-associated virus (AAV) is

extremely popular and extensively applied. This is

because of its characteristics including high

infectivity, low immunogenicity, and a minimal

probability of integrating into the human genome.

In the course of the research, two different AAV

vectors have been used to encapsulate the amyloid

precursor protein with the Swedish mutation

(APPsw)-specific gRNA and the Cas9 protein.

These are targeted at the KM670/671NL mutation

of the APP, a mutation that is of great significance

in the pathological process of Alzheimer's disease.

In both in vitro primary neuronal cell cultures and

in vivo Tg2576 mouse experiments, the production

of Aβ was reduced by approximately 60%.

However, the packaging capacity of AAV is limited

to only about 4.7kb, making it difficult to package

some larger genes. LV can accommodate longer

DNA insertion fragments (8 - 10kb), but its

propagation efficiency in the brain is low, and there

are risks of immunogenicity and gene integration.

AdV can efficiently express genes, but it has a

strong immunogenicity, which may trigger severe

immune responses (Gao et al. 2021, Wang et al.

2022, Sun et al. 2020). Non - viral carriers like

DNA nanocages can be fabricated via rolling circle

amplification. They are capable of carrying

sgRNA/Cas9 complexes and exhibit favorable

stability along with efficient cellular uptake

properties. In one study, DNA nanocages loaded

with the sgRNA/Cas9 complex targeting enhanced

green fluorescent protein (EGFP) were locally

injected into the tumors of EGFP tumor - bearing

mice. After 10 days, the expression of EGFP

decreased by about 25%, providing new insights for

the delivery in AD treatment. However, DNA

nanocages may also induce immunogenic reactions,

requiring further study (Chen et al. 2021).

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4 CRISPR/CAS9 GENE EDITING

TECHNOLOGY

The CRISPR/Cas9 system, which has its roots in

the adaptive immune mechanism of bacteria and

archaea, is engineered to precisely identify and

effectively neutralize invading bacteriophages or

other foreign nucleic acid entities. The CRISPR/Cas9

system primarily consists of the Cas9 protein and

single-guide RNA (sgRNA). The sgRNA, in

accordance with the base-pairing principles, guides

the Cas9 protein to the specific target DNA sequence

and performs cleavage on the double strands of the

DNA. The Cas9 protein consists of multiple distinct

structural domains. Among them are REC I, REC II,

the bridge helix, the PAM-interacting domain, HNH,

and RuvC, among others. The PAM sequence is of

vital importance in the process of Cas9 recognizing

the target DNA (Jinek et al. 2020). From the

perspective of its development, the CRISPR/Cas9

technology has gone through a process from its initial

discovery to its gradual application in the genome

editing of mammals. In 1987, Ishino et al. first

discovered CRISPR sequences in Escherichia coli,

but their function was not clear at the time.

Subsequently, following several years of intensive

research, in 2012, two separate laboratories

independently verified that the CRISPR/Cas system

reconstituted in vitro indeed has the biological

capability to cleave a specific single DNA sequence.

In 2013, three independent American teams

successfully utilized Cas9 to edit bacterial and

mammalian genomes. Subsequently, the

CRISPR/Cas9 technology experienced a swift

progression and has been widely applied in the field

of genetic engineering (Ishino et al. 2020, Ran et al.

2021).

When compared to other gene - editing

technologies such as Zinc Finger Nucleases (ZFN),

Transcription Activator - Like Effector Nucleases

(TALEN), and meganucleases, the CRISPR/Cas9

technology has significant advantages. These include

a relatively simple operation process, high efficiency,

and lower cost. During the gene editing process, the

CRISPR/Cas9 system recognizes the target DNA

sequence through the sgRNA, and the design process

of the sgRNA is quite straightforward. In contrast,

both Zinc Finger Nucleases (ZFN) and Transcription

Activator-Like Effector Nucleases (TALEN)

necessitate intricate protein design and construction

procedures. Moreover, CRISPR/Cas9 exhibits a

greater editing efficiency and is capable of attaining

effective gene editing across a diverse range of cells

and organisms. Regarding the cost aspect, the

reagents and equipment needed for CRISPR/Cas9

technology are relatively widely available and

common. This availability leads to a reduction in the

overall expenses associated with research and

practical application.

During the process of gene editing, upon the

Cas9 protein's recognition of the target gene

sequence, the CRISPR/Cas9 system induces

double-strand breaks within that specific sequence.

Following that, the cell proceeds with the repair

process through either the non-homologous end

joining (NHEJ) or the homology-directed repair

(HDR) mechanism. NHEJ serves as the primary

mechanism for mending double-strand breaks in the

cellular DNA. It directly links the ends of the

fragmented chromosomal DNA. However, this

process is prone to mistakes. There is a likelihood

of random insertions or deletions (indels) of

nucleotides, which in turn can lead to gene

disruption. In contrast, HDR repairs DNA through

the process of homologous recombination. It

precisely rectifies DNA breaks by substituting

mutated or incorrect sequences with the accurate

ones. Nevertheless, the efficiency of HDR is

relatively low and it predominantly occurs during

the S or G2 phases of the cell cycle. In practical

applications, depending on various research goals

and needs, the appropriate repair pathway can be

selected to achieve gene knockout, insertion, or

correction. CRISPR/Cas9 causes double - strand

breaks in the target DNA, and these breaks are

repaired through either the NHEJ or HDR

pathways. NHEJ directly ligates broken DNA ends,

prone to errors causing indels. HDR repairs breaks

accurately during S or G2 phases, but with lower

efficiency. Choice of pathway depends on research

goals for gene knockout, insertion, or correction.

5 ANIMAL MODEL

CONSTRUCTION

In order to have a deeper comprehension of the

pathological mechanisms that underlie AD, the

CRISPR/Cas9 technology has been utilized to create

AD animal models. For instance, through the

utilization of this technology, researchers have

inserted specific mutations including F681Y, G676R,

and R684H into the amyloid precursor protein (APP)

gene of mice and rats. As a result, they have

successfully created humanized animal models.

These carefully crafted animal models offer potent

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tools for the investigation of amyloid precursor

protein (APP) processing. They are of vital

importance in uncovering and revealing novel

pathological mechanisms of AD. In the process of

establishing cell models, the CRISPR/Cas9

technology has also had a significant impact. For

example, Wang and his co-researchers made use of

the CRISPR/Cas9 system to lower the concentration

of thioredoxin-interacting protein (Txnip) within

HT22 cells. This method successfully alleviated the

protein cysteine oxidation modification induced by

amyloid β, indicating that Txnip might have the

potential to be an effective target for the therapy of

AD. CRISPR/Cas9 technology has been used in

constructing both AD animal and cell models. In

animal models, specific mutations were introduced

into the APP gene of mice and rats to create

humanized models for studying APP processing and

AD pathology. In cell models, Wang et al.

downregulated Txnip in HT22 cells with this

technology, suggesting Txnip as a potential AD

treatment target. Song et al. determined that reducing

the expression of KIBRA in HT22 cells impacts cell

growth and apoptosis and elicits a response to Aβ1 -

42 oligomers. Sun et al., on the other hand, utilized

CRISPR/Cas9 to knockout the PSEN1 gene in N2a

cells. Their findings indicated that the introduction of

exogenous PSEN1 mutant protein led to a reduction

in the production of Aβ42 and Aβ40. However, due

to differences between these cell lines and real

neurons, the constructed AD models can't accurately

clarify the molecular mechanisms of AD onset. So,

the induced pluripotent stem cells (iPSCs) that are

derived from patients have been attracting more and

more attention. In 2016, Paquet and his research team

introduced mutations into the APP and PSEN1

genes—genes linked to the development of AD—

within human induced pluripotent stem cells (iPSCs).

Subsequently, they detected higher levels of Aβ in

neurons derived from both homozygous and

heterozygous human iPSCs carrying the mutations.

This indicated that CRISPR/Cas9 technology could

simulate AD-related mutations in human neuronal

cells.

In terms of animal model construction, in addition

to the models introduced above with APP mutations

in mice and rats, other studies have utilized

CRISPR/Cas9 technology to construct different

models. As Komor and his colleagues utilized the

CRISPR/Cas9 system to convert APOE3r into

APOE4, they carried out point mutation

modifications within mouse astrocytes (Kim et al.

2020). Park and his associates administered Cas9

nanocomplexes that were targeted at the tyrosine

hydroxylase (Th) and BACE1 genes to the primary

neurons of mice. They then assessed the efficiency of

these Cas9 nanocomplexes and discovered that there

were almost no off-target effects. Furthermore, they

administered the Cas9-BACE1 nanocomplex into the

hippocampus of 6-month-old mice with AD.

Afterward, they observed that, four weeks following

the injection, the expression levels of BACE1 as well

as the β-cleavage products of the amyloid precursor

protein (APP) in the hippocampus had significantly

dropped. Takalo and his colleagues devised a Plcγ2 -

P522R knock - in mouse model. Subsequently, they

conducted an evaluation of the protective effect that

this specific variant had. They found that the Plcγ2 -

P522R knock-in mice exhibited enhanced microglial

function, providing a new potential avenue for the

treatment of AD. Takalo and his collaborators created

a Plcγ2 - P522R knock - in mouse model and then

evaluated the protective effect this variant exerted.

They discovered that the Plcγ2 - P522R knock - in

mice demonstrated augmented microglial function,

thus presenting a novel potential approach for the

treatment of AD. Although there is currently no AD

primate model designed through CRISPR/Cas9

technology, studies have successfully achieved

genetic modification in the crab-eating macaque. In

the future, constructing an AD primate model based

on CRISPR/Cas9 technology will help to delve

deeper into the pathogenesis of AD and promote the

progress of AD treatment research. CRISPR/Cas9

technology has not yet been used to create an AD

primate model, but it has been used to genetically

modify crab-eating macaques. Future models based

on this technology could advance understanding of

AD pathogenesis and treatment research.

6 CONCLUSION

CRISPR/Cas9 technology has achieved substantial

headway in the research regarding Alzheimer's

disease (AD) treatment. In terms of gene editing,

editing strategies targeting key genes such as APP,

BACE1, and APOE have shown potential in reducing

Aβ levels and improving AD pathology. By

constructing AD animal models, a powerful tool has

been provided for in-depth research into the

pathogenesis of AD, and certain achievements have

been made in screening pathogenic genes and

exploring the role of inflammatory molecules in AD.

However, CRISPR/Cas9 technology still faces

numerous challenges in the clinical application for

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AD treatment. In terms of delivery systems, both viral

vectors and non-viral vectors have their own

limitations. For instance, viral vectors face issues

with immunogenicity and packaging capacity, while

non-viral vectors encounter challenges with blood-

brain barrier (BBB) penetration and cellular uptake

efficiency. Moreover, the off - target effects inherent

in CRISPR/Cas9 technology have the potential to

trigger unforeseen genetic alterations, thereby

impinging on the safety and effectiveness of

treatment. Furthermore, the long-term safety and

ethical issues of this technology also need to be

further explored and studied.

In the future, it will be necessary to further

optimize the delivery system of CRISPR/Cas9

technology, enhance its targeting and delivery

efficiency, and reduce its immunogenicity. The

pursuit of more accurate gene editing approaches is

crucial for minimizing the incidence of off - target

effects. Moreover, surmounting the hurdles related to

blood - brain barrier penetration and enhancing the

cellular uptake efficiency of non - viral vectors are

essential steps for the progress of gene therapy

applications within the central nervous system.

Moreover, continuous research is required to assess

the long-term safety and address the ethical concerns

surrounding the use of CRISPR/Cas9 technology,

ensuring its safe and effective translation into clinical

practice. Despite these obstacles, the potential of

CRISPR/Cas9 technology in revolutionizing AD

treatment remains promising. Efforts are underway to

refine the technology, address its limitations, and

harness its full potential. With ongoing advancements

and a deeper understanding of AD pathogenesis, the

hope is that CRISPR/Cas9-based therapies will

eventually offer new avenues for treating this

devastating disease, bringing relief to patients and

their families.

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