The Role of PP2A in the Pathological Mechanisms of Alzheimer’s

Disease and Advances in Its Therapeutic Applications

Ketong Qian

Dulwhich College Suzhou, Jiangsu, China

Keywords: Protein Phosphatase 2A (PP2A), Alzheimer's Disease, Therapeutic Target.

Abstract: Alzheimer’s disease (AD), a neurodegenerative disorder of the central nervous system, has become a pressing

global health concern. The increasing incidence of AD, driven by an aging population, imposes significant

socioeconomic burdens. Despite decades of research, the exact etiology and molecular mechanisms of AD

remain unclear, limiting the development of effective treatments. It regulates key processes such as cell cycle

progression, apoptosis, and signal transduction. Recent studies highlight its crucial role in AD

pathophysiology, particularly in tau dephosphorylation and Aβ metabolism. Dysfunctional PP2A activity has

been implicated in tau hyperphosphorylation, a major contributor to neurofibrillary tangle formation, and in

the dysregulation of Aβ clearance. Investigating the role of PP2A in AD pathogenesis provides valuable

insights into disease mechanisms and potential therapeutic targets. This review discusses the structural and

functional aspects of PP2A, its contribution to AD pathology, and emerging therapeutic strategies aimed at

modulating PP2A activity. Understanding these aspects may lead to the development of innovative

approaches for early diagnosis, precision medicine, and disease prevention, ultimately improving patient

outcomes.

1 INTRODUCTION

Alzheimer’s disease (AD), a neurodegenerative

disorder of the central nervous system, has become a

growing global health challenge (Benmelouka, et al.,

2022). With accelerated population aging worldwide,

the incidence of AD has risen significantly, imposing

heavy burdens on families and societies.

The primary pathological features of AD include

extracellular β-amyloid (Aβ) plaques, intracellular

neurofibrillary tangles (NFTs) caused by

hyperphosphorylation of tau protein, neuronal loss,

and synaptic dysfunction. Despite decades of research

into AD pathogenesis, its exact etiology and

mechanisms remain unclear, resulting in limited

effective treatments (Tiwari, et al., 2019).

Protein phosphatase 2A (PP2A), a ubiquitously

expressed serine/threonine phosphatase with critical

biological functions, regulates diverse cellular

processes, including cell cycle progression,

proliferation, differentiation, and apoptosis

(Swerdlow, et al., 2023). Recent studies highlight

PP2A’s pivotal role in AD pathophysiology.

In-depth investigation of PP2A’s role in AD

pathogenesis will not only advance our understanding

of the disease but also provide novel theoretical

insights and potential therapeutic targets. Elucidating

the relationship between PP2A and AD pathology

may enable interventions to modulate PP2A activity,

offering new avenues for early diagnosis, precision

therapy, and disease prevention. Thus, systematic

research on PP2A’s role in AD mechanisms and its

therapeutic applications holds profound scientific and

practical significance.

2 STRUCTURAL AND

FUNCTIONAL BASIS OF PP2A

2.1 Molecular Architecture of PP2A

PP2A is a heterotrimeric enzyme composed of a

structural subunit A (scaffold), a catalytic subunit C,

and a regulatory subunit B. Subunit A, characterized

by its helical repeat structure, provides a platform for

binding subunits B and C, ensuring structural stability

(Dentoni, et al., 2022). Subunit C contains a

conserved catalytic site essential for phosphatase

Qian, K.

The Role of PP2A in the Pathological Mechanisms of Alzheimer’s Disease and Advances in Its Therapeutic Applications.

DOI: 10.5220/0014436900004933

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 149-154

ISBN: 978-989-758-789-4

149

activity, while regulatory B subunits confer substrate

specificity and subcellular localization.

2. Structure and Functional Basis of PP2A

2.2 Review of Molecular Structure

Studies on PP2A

PP2A, as a protein phosphatase that plays a critical

role in cellular physiological processes, has been a

major focus of research in this field. A deeper

understanding of the molecular structure of PP2A is

essential for elucidating its mechanisms in normal

physiological functions and disease development.

Structural subunit A, also known as subunit A,

features a unique double-helical repeat structure that

provides a binding platform for catalytic subunit C

and regulatory subunit B, playing an indispensable

role in maintaining the overall structural stability of

the PP2A holoenzyme (Dentoni, et al., 2022). This

double-helical repeat structure organizes the subunits

in an orderly manner, ensuring proper interactions

among them and thereby supporting the normal

function of the PP2A holoenzyme.

Catalytic subunit C is the core component

responsible for the phosphatase activity of PP2A. Its

structure contains multiple functional regions that

precisely regulate catalytic activity. The active site of

catalytic subunit C is highly conserved and can

specifically recognize and bind phosphate groups on

substrates, removing them through hydrolysis to

regulate the phosphorylation state of substrate

proteins. Studies have shown that even minor changes

in the active site of catalytic subunit C can

significantly affect the catalytic activity of PP2A,

thereby influencing the normal operation of

numerous intracellular signaling pathways.

Regulatory subunit B exhibits diversity, with

different types of regulatory subunits B conferring

distinct substrate specificity and intracellular

localization to the PP2A holoenzyme. By interacting

with structural subunit A and catalytic subunit C,

regulatory subunit B finely tunes the affinity of the

PP2A holoenzyme for specific substrates and its

catalytic activity. Different regulatory subunits B are

expressed at varying levels in different tissues and

cell types, enabling PP2A to perform diverse

functions under various physiological and

pathological conditions.

In recent years, these techniques have provided

powerful tools for understanding the subunit

composition, subunit interactions, and three-

dimensional structure of the PP2A holoenzyme.

Through these studies, the understanding of the

molecular structure of PP2A has deepened, laying a

solid foundation for further exploration of its

functions in physiological and pathological

processes.

2.3 Research on the Normal

Physiological Functions of PP2A

PP2A, as a phosphatase in cellular physiological

processes, has broad and complex normal

physiological functions. These functions are essential

for maintaining intracellular homeostasis.

In the regulation of cellular signal transduction,

PP2A acts as a precise "regulator." The accurate

operation of numerous intracellular signaling

pathways relies on the dynamic balance between

protein phosphorylation and dephosphorylation.

PP2A can specifically remove phosphate groups from

certain proteins, thereby terminating or modulating

signal transmission (Del, et al., 2017). For example,

in growth factor signaling pathways, when cells

receive growth factor stimulation, a series of proteins

undergo phosphorylation and activation, promoting

signal transmission related to cell growth and

proliferation. PP2A plays a timely role by

dephosphorylating these activated proteins,

preventing excessive signal activation and ensuring

that cell growth and proliferation remain within

normal regulatory limits, thereby avoiding abnormal

cell proliferation and diseases such as cancer.

The normal progression of the cell cycle also

depends on the fine regulation of PP2A. The cell

cycle is a highly ordered process involving strict

regulation at multiple key checkpoints. PP2A plays

different roles at various stages of the cell cycle.

During the G1 phase, it participates in regulating the

activity of cyclin-dependent kinase (CDK)

complexes, influencing whether cells enter the S

phase for DNA replication. During mitosis, PP2A is

indispensable for spindle assembly and proper

chromosome separation. By regulating the

phosphorylation state of related proteins, PP2A

ensures the correct connection between spindle

microtubules and chromosomes and the accurate

separation of sister chromatids, guaranteeing the

precision and stability of cell division.

Additionally, PP2A plays a crucial role in

maintaining cytoskeletal stability. The cytoskeleton is

a network of protein fibers within cells that is

essential for maintaining cell shape, movement, and

intracellular transport. PP2A regulates the

phosphorylation levels of cytoskeleton-related

proteins, influencing the dynamic balance between

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cytoskeletal assembly and disassembly (Reddy et al.,

2011). When cells undergo morphological changes or

migration in response to external stimuli, PP2A can

promptly adjust the phosphorylation state of

cytoskeleton-related proteins, facilitating cytoskeletal

remodeling to meet cellular physiological needs.

In summary, the normal physiological functions

of PP2A broadly encompass cellular signal

transduction, cell cycle regulation, and cytoskeletal

stability, among other critical aspects. These

functions work together to maintain the normal

physiological state of cells and organisms. A deeper

understanding of the normal physiological functions

of PP2A provides a solid foundation for further

exploration of its role in disease development.

3 RESEARCH ON THE ROLE OF

PP2A IN THE PATHOLOGICAL

MECHANISMS OF AD

3.1 Review of the Relationship between

PP2A and Aβ Protein Metabolism

The relationship between PP2A and Aβ protein

metabolism is a key aspect of understanding the

pathological mechanisms of AD. The abnormal

metabolism of Aβ protein plays a central role in the

pathogenesis of AD, and the role of PP2A in this

process has become a focus of research.

In terms of Aβ production, abnormal processing

of the amyloid precursor protein (APP) is a major

cause of increased Aβ generation. PP2A can regulate

the activity of related proteases, influencing the

cleavage process of APP (Patro, et al., 2021). Some

studies have found that when PP2A activity is

reduced, particularly the neurotoxic Aβ42. This

process involves complex cellular signaling pathways

and molecular interaction networks, with PP2A as a

key regulatory factor. Dysfunction of PP2A may

disrupt the normal balance of APP processing,

leading to excessive Aβ production.

In terms of Aβ aggregation, PP2A also has a

significant impact. The aggregation of Aβ into

oligomers and fibrillar deposits is one of the

neuropathological features of AD. Research indicates

that PP2A can interact with Aβ, influencing its

aggregation kinetics. When PP2A functions

normally, it may inhibit Aβ aggregation, reducing the

formation of oligomers and fibrils. However, when

PP2A activity is inhibited or its expression is

abnormal, Aβ is more prone to aggregate, forming

neurotoxic structures that impair neuronal function.

Furthermore, PP2A plays a role in the clearance

of Aβ protein. Under normal conditions, the body has

multiple mechanisms for clearing Aβ, including

transport across the blood-brain barrier and

phagocytosis by microglia. PP2A can regulate related

intracellular signaling pathways, affecting the

phagocytic ability of microglia and the transport

function of the blood-brain barrier. When PP2A

function is impaired, the efficiency of Aβ clearance

may decrease, leading to its accumulation in the brain

and exacerbating neuropathological damage.

In conclusion, PP2A is closely related to Aβ

protein metabolism. In-depth research on the

relationship between PP2A and Aβ protein

metabolism will help further elucidate the

pathogenesis of AD and provide a theoretical basis

for developing therapeutic strategies targeting

abnormal Aβ metabolism. Future studies should

further clarify the specific molecular mechanisms of

PP2A in various aspects of Aβ metabolism and

explore how to modulate PP2A function to intervene

in abnormal Aβ metabolism, thereby opening new

avenues for AD treatment.

3.2 Research on the Relationship

between PP2A and Tau Protein

Hyperphosphorylation

In the pathological mechanisms of AD, the

hyperphosphorylation of tau protein plays a critical

role, and there is a complex and close relationship

between PP2A and tau protein hyperphosphorylation.

Tau protein plays a crucial role in maintaining the

normal structure and function of neurons. However,

in the brains of AD patients, tau protein becomes

excessively phosphorylated, forming neurofibrillary

tangles (NFTs), which are a key pathological feature

of AD (Leal, et al., 2020). The accumulation of NFTs

disrupts the cytoskeletal structure within neurons,

leading to neuronal dysfunction and death, and

ultimately contributing to cognitive decline.

PP2A plays a key role in regulating the

phosphorylation levels of various intracellular

proteins, including tau protein. Studies have shown

that changes in PP2A activity are closely related to

tau protein hyperphosphorylation. Under normal

physiological conditions, PP2A can promptly remove

excess phosphate groups from tau protein,

maintaining the dynamic balance.

However, in the brain tissues of AD patients,

PP2A activity is significantly reduced. Various

The Role of PP2A in the Pathological Mechanisms of Alzheimer’s Disease and Advances in Its Therapeutic Applications

151

factors can lead to decreased PP2A activity, such as

the upregulation of endogenous PP2A inhibitors in

the brains of AD patients, which bind to and inhibit

PP2A, reducing its ability to dephosphorylate tau

protein and resulting in tau hyperphosphorylation.

Additionally, pathological processes such as

oxidative stress may also affect the structure and

function of PP2A, further reducing its activity.

At the same time, hyperphosphorylated tau

protein may, in turn, affect PP2A. Overly

phosphorylated tau protein may interfere with the

subcellular localization of PP2A or affect its

interactions with other regulatory proteins, further

disrupting the normal function of PP2A and creating

a vicious cycle.

In-depth research on the relationship between

PP2A and tau protein hyperphosphorylation will help

us better understand the pathogenesis of AD. This not

only provides new perspectives for elucidating the

pathological processes of AD but also offers potential

targets for developing therapeutic strategies. By

modulating PP2A activity, it may be possible to

correct tau protein hyperphosphorylation, thereby

delaying or preventing the progression of AD, which

has significant theoretical and clinical implications

for AD treatment.

4 ADVANCES IN PP2A-BASED

AD THERAPEUTIC

APPLICATIONS

4.1 Review of Drug Development

Targeting PP2A

Drug development targeting PP2A has garnered

significant attention in the field of AD treatment. As

research into the pathological mechanisms of AD

deepens, PP2A has emerged as a key regulatory

molecule and a promising drug target.

In recent years, numerous research teams have

focused on developing drugs targeting PP2A. Some

studies have concentrated on small-molecule

compounds, aiming to precisely modulate PP2A

activity to intervene in the pathological processes of

AD (Markovinovic, et al., 2022). These small-

molecule drugs can specifically bind to certain

structural domains of PP2A, altering its conformation

and thereby affecting its interactions with substrates,

ultimately regulating related signaling pathways. For

example, some small-molecule drugs can enhance

PP2A's dephosphorylation of tau protein.

At the same time, natural products and their

derivatives have become an important source of drug

development targeting PP2A. Many plant extracts

contain components with potential PP2A-modulating

activity. Through isolation, identification, and

structural modification, these components hold

promise for developing novel AD treatments. Certain

flavonoids have been found to activate PP2A,

improving Aβ protein metabolism and reducing Aβ

amyloid plaque deposition, offering new approaches

for AD treatment.

In the field of antibody drug development,

progress has also been made. By generating

monoclonal antibodies targeting specific epitopes of

PP2A, its function in vivo can be precisely regulated.

These antibodies can specifically block PP2A's

interactions with certain pathogenic factors or

enhance its binding to beneficial regulatory

molecules, thereby exerting therapeutic effects.

However, drug development targeting PP2A is

not without challenges. PP2A is involved in

numerous physiological processes within cells, and

excessive or inappropriate modulation of its activity

may lead to a range of side effects. Therefore,

achieving precise regulation of PP2A activity to

effectively treat AD while avoiding adverse effects is

a major challenge. Additionally, issues such as the

pharmacokinetic properties of drugs and their ability

to cross the blood-brain barrier require further

research and optimization. Despite these challenges,

drug development targeting PP2A offers new hope

for AD treatment. With continuous technological

advancements and deeper research, safer and more

effective therapeutic drugs may be developed,

bringing benefits to AD patients.

4.2 Research on the Application of

PP2A as a Diagnostic Biomarker

for AD

In the early diagnosis and monitoring of AD,

identifying effective diagnostic biomarkers is crucial.

PP2A, as a protein phosphatase that plays a critical

role in cellular physiological processes, has recently

gained attention in research on its application as a

diagnostic biomarker for AD (Wong, et al., 2017).

Multiple studies have shown that PP2A exhibits

different expression patterns and activity changes in

the brain tissues and body fluids of AD patients

compared to healthy individuals. In brain tissues,

techniques such as immunohistochemistry and

Western blotting have revealed significantly reduced

PP2A protein levels and activity in specific regions of

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AD patients' brains, such as the hippocampus and

temporal cortex. These changes are closely associated

with the formation of AD neuropathological features

like Aβ plaques and tau protein tangles. This suggests

that changes in PP2A levels and activity may be

involved, making it a potential diagnostic biomarker.

In body fluids, blood and cerebrospinal fluid

(CSF) are the primary focuses of research. Analysis

of blood samples from AD patients has shown that

plasma levels of PP2A-related protein subunits are

associated with disease severity. As the disease

progresses, the levels of certain PP2A subunits

undergo significant changes, offering the possibility

of early AD screening through blood tests. In CSF

studies, differences in PP2A activity and related

metabolite concentrations have been observed

between AD patients and healthy controls. These

differences can appear, serving as sensitive indicators

for early AD diagnosis.

Additionally, the PP2A is also reflected in its

combined use with other known diagnostic markers.

When used alongside traditional markers like Aβ42

and tau protein, PP2A-related indicators can improve

the accuracy and specificity of AD diagnosis (Schuiki

et al., 2009). By constructing multi-marker diagnostic

models, a more comprehensive assessment of an

individual's risk of developing AD can be achieved,

providing stronger support for clinical diagnosis and

disease evaluation.

However, challenges remain in using PP2A as a

diagnostic biomarker for AD (Yeo, et al., 2021). For

example, differences in detection methods and

sample sources across studies have led to

heterogeneity in results, necessitating the

standardization of detection methods and sample

collection procedures. Additionally, the mechanisms

underlying the dynamic changes of PP2A during AD

development require further research to better

understand its biological basis as a diagnostic

biomarker. Despite these challenges, the potential of

PP2A as a diagnostic biomarker offers new directions

for the early diagnosis and intervention of AD. With

continued research, breakthroughs in AD diagnosis

may be achieved.

5 CONCLUSION

In the field of PP2A and AD research, numerous

scholars have conducted extensive and fruitful work,

providing a solid foundation for a deeper

understanding of PP2A's role in AD pathological

mechanisms and its applications.

In terms of the structure and functional basis of

PP2A, research on its molecular structure has been

thorough, clearly revealing the unique composition

and architecture of PP2A. This has laid the

groundwork for further exploration of its functions in

physiological and pathological states. Progress has

been adopted in studying the normal physiological

functions of PP2A, clarifying its indispensable role in

key processes such as cellular signal transduction and

metabolic regulation.

Regarding the role of PP2A in AD pathological

mechanisms, research on the relationship between

PP2A and Aβ protein metabolism has yielded

substantial results. Numerous studies have shown that

changes in PP2A activity are closely related to the

production, aggregation, and clearance of Aβ protein,

providing new perspectives for understanding

abnormal Aβ metabolism in AD pathogenesis.

Important breakthroughs have also been made in

research on the relationship between PP2A and tau

protein hyperphosphorylation, revealing that PP2A

activity imbalance may be a key factor leading to tau

protein hyperphosphorylation.

In the application of PP2A-based AD treatments,

research on drug development targeting PP2A is

actively advancing. Many studies are focused on

screening and developing drug molecules that can

modulate PP2A activity, with some drugs showing

therapeutic potential in animal experiments.

Additionally, new discoveries have been made in the

application of PP2A as a diagnostic biomarker for

AD, with changes in its expression levels in blood or

CSF holding promise for the diagnosis and

intervention.

However, despite the achievements of existing

research, there are still some limitations. Future

research should further explore the complex

molecular regulatory networks of PP2A in AD

pathogenesis, strengthen interdisciplinary research,

improve the success rate of PP2A-targeted drug

development, and validate the clinical value of PP2A

as a diagnostic biomarker. Through these efforts, new

breakthroughs in AD treatment and diagnosis may be

achieved.

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