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American Journal of  
Chemistry and Pharmacy (AJCP)

Chemical Modulation of  Amyloid Beta Oligomer’s in Alzheimer’s Disease
Muhammad Jehangir1*, Sayyad Muhammad2, Muhammad Tayyab3, Wajid Ali3, Ali Danish Alvi3,. Muhammad Naveed4

Volume 4 Issue 1, Year 2024
ISSN: 2834-0116 (Online)

DOI: https://doi.org/10.54536/ajcp.v4i1.4886
https://journals.e-palli.com/home/index.php/ajcp

Article Information ABSTRACT

Received: April 01, 2025
Accepted: May 03, 2025
Published: June 15, 2025

Amyloid beta oligomers play a key role in the pathophysiology of  Alzheimer’s disease. Since 
it contributes to memory and neuronal loss, cognitive decline, degradation of  neurons as 
well as diseases progression. As Aβ oligomer is very small and heterogeneous and it can 
change from one shape to another shape therefore it has various kinds of  morphologies 
including monomers, oligomers and fibrils. Due to instable behavior of  these proteins, it’s 
very difficult to understand its exact mechanism. In this concise review, information over the 
past seven years concentrated on the molecular characteristics of  amyloid-β oligomers has 
been summarized along with two pathways involving protein aggregation and condensation. 
Furthermore, metal complexes, immunotherapies, and anti-Aβ antibodies are reported 
here, which can modulate aggregation, stabilize non-toxic forms, and enhance degradation. 
Finally, new discoveries on small molecules that control, modify and inhibit the progression 
of  amyloid-β oligomers are integrated, as these are key characteristics of  Alzheimer’s disease.

Keywords
Alzheimer’s Diseases, Aβ 
Oligomer’s, Degradation, Protein 
Aggregation and Condensation, 
Stabilization

1 School of  Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, P. R. China
2 Department of  Chemical Engineering, Nanjing Tech University, Nanjing 211816, P. R. China
3 School of  Pharmaceutical science, Nanjing Tech University, Nanjing 211816, China
4 School of  Biological and Pharmaceutical Engineering, Nanjing Tech University, P.R. China
* Corresponding author’s e-mail: jehangirm62@gmail.com

INTRODUCTION
According to recent projections, the number of  people 
living with Alzheimer disease (AD), the most prevalent 
form of  dementia, is expected to reach 87 million by 2050. 
Age is the primary risk factor for AD, which currently 
affects more than 35 million people worldwide (Hwang 
et al., 2019; Tzioras et al., 2022). Given that 50–80% of  
all cases among the elderly population are estimated 
to be related to this rapidly ageing population, it has 
emerged as a significant social issue (Peng et al., 2019). 
Aberrant protein aggregation, which affects synaptic 
signaling, mitochondrial function, neuroinflammation, 
and neuronal loss, is indicative of  AD and leads to 
multifactorial neuronal dysfunction (Limbocker et al., 
2019). Alzheimer’s disease (AD) is caused by misfolded 
tau and amyloid-beta (Aβ) proteins that build up in 
the brain along harmful pathways that cause selective 
neuronal death and synaptic loss (Figure 1) (Senapati et 
al., 2023). The primary neurotoxic species responsible 
for the onset of  Alzheimer’s disease (AD) are oligomeric 
aggregates of  amyloid-β peptides (Aβ). Aβ oligomers 
stimulate additional pathological processes of  AD, 
including tau hyperphosphorylation, oxidative stress, and 
mitochondrial dysfunction, in addition to causing various 
neuronal dysfunctions like loss of  memory and learning. 
Thus, it is acknowledged that Aβ oligomers are suitable 
targets for AD diagnosis and treatment (Sehar et al., 2022). 
In the pathophysiology of  AD and other tauopathies, 
tauOs and tau filaments may be crucial players. The 
general consensus is that smaller, diffusible oligomers are 
more likely to be involved in AD pathogenesis than the 
larger tau assemblies, which include straight filaments, 
PHF, NFT, and ghost tangles, which are thought to be 
less toxic (Penke et al., 2020). Compared to amyloid fibrils, 

soluble Aβ oligomers have a stronger correlation with the 
advancement of  disease. For this reason, focusing on these 
oligomers may prove to be a useful therapeutic approach 
in the management and prevention of  Alzheimer’s 
(Jehangir et al., 2024). Finding Aβo in biological samples, 
like blood or cerebrospinal fluid, has enormous potential 
for tracking the development of  AD and providing an 
early diagnosis. But because Aβo are dynamic, structurally 
complex, and rare, it’s still very difficult to detect them 
accurately (Penke et al., 2020). Many of  these disease-
associated proteins not only misfold and aggregate, but 
also go through liquid-liquid phase separation (LLPS) 
to create dynamic condensates, which are essential for 
regular cellular processing (Muhammad et al., 2024). 
Many studies suggest that LLPS plays a significant role 
in the deposition and aggregation of  tau and amyloid-β 
and is closely linked to the pathophysiology of  AD. 
Investigating the fundamental mechanism in greater detail 
will help increase the rate of  early AD detection, which 
will lead to the development of  anti-AD medications 
and better outcomes for AD patients (Muhammad et al., 
2024). In this concise review, we gathered information 
over the past seven years and concentrated on the 
molecular characteristics of  amyloid-β oligomers, along 
with two pathways involving protein aggregation and 
condensation. We also integrated new discoveries on 
small molecules that control, modify, and break down 
amyloid-β oligomers, which are key characteristics of  
Alzheimer’s disease. Finally, we touched on their roles in 
the pathophysiology of  the disease. It is known that Aβ 
oligomers are the target of  studies on chemical regulatory 
mechanisms, stabilization, and degradation processes, 
as well as the role of  phase separation in Alzheimer’s 
disease.



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LITERATURE REVIEW
Amyloid-β Oligomers, Protein Aggregation and 
Condensation
 Soluble AβO can start to accumulate in the brain up to 
two decades before clinical symptoms appear (Hector 
& Brouillette, 2021). Aβ is produced as a result of  the 
amyloid precursor protein’s proteolytic cleavage by β- 
and γ-secretases. The two most prevalent forms of  Aβ 
in human bodies are Aβ40 and Aβ42. Aβ42 was found 
to be more likely to aggregate, despite the fact that 
Aβ40 and Aβ42 only differ by two amino acid residues. 
Aβ has a tendency to form a variety of  self-assembly 
structures, from mature fibrils to oligomers and as well 
as monomer’s (Volynsky et al., 2025). Aβ toxicity has been 
shown to be primarily caused by Aβ1~42 oligomers, both 
in vitro and in vivo (Han et al., 2025). Experimentally and 
computationally characterizing the early Aβ oligomers 
is a difficult task. Since most experimental observations 
provide time- and space-averaged properties, the transient 
and heterogeneous ensemble of  oligomer structures 
presents an experimental challenge (Derreumaux et al., 
2022). At physiological concentrations of  1–20 nM, Aβ42 
synthesis easily forms oligomeric structures, and the 
rate of  oligomer formation is temperature-dependent. 
At physiological concentrations, the formation of  
Aβ42 oligomers is a kinetically analyzed and inhibitable 
process that is repeatable (Li et al., 2023). The most 
neurotoxic agents are thought to be Aβ42 oligomers. 
The morphologies of  these oligomeric intermediates are 
diverse, encompassing spherical, annular, β-barrel, and 
protofibrillar forms, all of  which have the potential to 
contribute differently to the toxicity of  Aβ (Foley et al., 
2019). In order to diagnose and treat AD, Aβ oligomers 
are accepted as valid targets. However, because the term 
“Aβ oligomer” can refer to a variety of  soluble Aβ species 
or a mixture of  different types of  metastable oligomeric 
species with different sizes, shapes, and conformations 
as a result of  Aβ’s dynamic assembly, it can be somewhat 
ambiguous (Viola & Klein, 2015). Various experiments 
have contributed to our current understanding of  the 

structures and biology of  Aβ oligomers, even though a 
unified model for their role in Alzheimer’s disease has 
not yet been developed. Studies using solid-state nuclear 
magnetic resonance (NMR) conducted by Paravastu and 
colleagues revealed that antiparallel β-sheets make up the 
oligomers of  Aβ (Haerianardakani et al., 2020). 

Protein Aggregation and Condensation
The word “aggregation” is frequently used in biology to 
refer to assemblies that are created under pathological 
circumstances, where the molecules within the aggregate 
are irreversibly disrupted and frequently regarded as 
pathogenic factors. One important feature of  biological 
processes that are irreversible is aggregation. In contrast, 
the word “condensation” describes dynamic, reversible 
molecules that can be redissolved to carry out their specific 
tasks; the intracellular environment is closely monitored 
during their assembly (Alberti & Hyman, 2021). But 
there is some degree of  interdependence between these 
two categories of  higher-order protein assemblers. 
Protein components can misfold and irreversibly 
aggregate when protein homeostasis is disrupted under 
pathological or pressure conditions, which can lead to 
an imbalance in biomolecular condensation and the 
uncontrollable collapse of  these structures. Aging or 
solidified condensates can then frequently transform into 
aggregates (Amzallag & Hornstein, 2022; Savastano et 
al., 2020). Protein condensates or aggregates may arise 
from intermediate clusters as precursors of  droplets or 
aggregates under certain circumstances. A droplet that 
forms as an intermediate aggregate and then transforms 
into a solid state is one more potential mechanism for 
protein aggregation (Wegmann et al., 2018). Nonetheless, 
a number of  investigations have indicated that amyloid 
(or cross-β) interactions play a role in the development 
of  protein aggregates, and the in vitro production of  
amyloid fibrils is commonly observed in phase-separated 
proteins (Hughes et al., 2018; Luo et al., 2018). Aside 
from nervous system conditions like schizophrenia, 
bipolar, and autism disorders, depression, epilepsy, and 

Figure 1: Amyloid-β (Aβ) misfolds and forms soluble toxic oligomers and fibrils that accumulate in the brain leading 
to synaptic loss and selective neuronal death



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Alzheimer’s and Parkinson’s diseases, the top-ranking 
protein condensation diseases also include depression. 
Synaptic condensate-forming proteins’ genes are linked 
to the majority of  these neurological disorders (Zeng et 
al., 2016). The growing body of  evidence indicates that a 
variety of  human diseases are probably caused by aberrant 
protein condensation. Changes in the physiological states 
of  proteins are the root cause of  these pathologies, which 
are collectively known as protein condensation diseases (Li 
et al., 2020). Yet, nucleation and off-pathway aggregation 
are frequently involved in the formation of  amyloid 
fibrils, which is not just a straightforward polymerization 
process. Delays cause disordered intermediates to refold 
into non-native secondary structures (β-strands), which 
are linked to the creation of  oligomers, during a lag 
phase. In certain cases, during the α-β structure transition, 
folding intermediates with extended (non-native) α-helices 
can form native or amyloid states (Žerovnik & Venko, 
2023). Because of  the stacking of  aromatic rings and a 
network of  backbone hydrogen bonds, amyloid fibrils, 
which are highly ordered and rigid protein states, can have 
a variety of  morphologies (Stanković et al., 2020; Taylor 
& Staniforth, 2022). Reversibility is one of  the main 
distinctions between protein condensates and aggregates. 
Protein condensates are at least initially reversible, in 
contrast to more toxic forms of  protein aggregates (Shin 
et al., 2017). A characteristic of  diseases like transmissible 
spongiform encephalopathies, prion diseases, Alzheimer’s 
disease, and Parkinson’s disease is protein aggregation. 
There is ongoing debate as to whether the aggregated 
proteins are involved in the pathological process directly 

or are merely bystanders. Consequently, it is crucial to 
comprehend PS and aggregation. It is becoming evident 
that the pathogenesis of  neurodegenerative disorders 
may involve proteins with liquid-to-solid transitions, 
such as Tau, α-synuclein, and TDP-43, which bind to 
RNA and are fused in sarcoma (FUS) (Zbinden et al., 
2020). The discovery of  liquid-like condensates raises the 
prospect of  a different route for amyloid aggregation. 
This “condensation pathway” is different from the 
“deposition pathway,” which is the direct formation of  
amyloid aggregates from their native state via oligomeric 
species. Even within the same cell and protein system 
going through self-assembly, solid deposits have been seen 
to form either directly through the deposition pathway or 
from liquid droplets through the condensation pathway 
(Cascella et al., 2022; Hardenberg et al., 2020). However, 
when amyloid aggregation occurs within condensates, 
the role of  oligomers is still unclear. Within a condensed 
gel-like phase, it was discovered that TDP-43 oligomers 
form in both the deposition and condensation pathways 
and before solid aggregates emerge (French et al., 2019). 
Furthermore, it has been documented that ⍺-synuclein 
oligomers were formed right after the monomeric protein 
underwent phase separation into a hydrogel. In this 
environment, monomers, oligomers, and fbrils coexist, 
and the hydrogels trap ⍺-synuclein in a highly cytotoxic 
state rather than releasing it (Kumar et al., 2018). Similarly, 
it was discovered that liquid–liquid phase separation causes 
a pathogenic conformation and oligomerization in tau and 
comes before gel formation and subsequently aggregation 
in vitro (Kanaan et al., 2020; Wegmann et al., 2018).

Figure 2: A synopsis of  condensation and the amyloid formation deposition pathway. 
Source: BioRender

Structural Features
Understanding the intricate structure of  Aβ(1-42)
oligomer’s is crucial, and in recent times, solid-state 
NMR-spectroscopy has been used to perform structural 
analyses on various oligomer preparations of  Aβ(1-42)
oligomer’s and Aβ(1-40)oligomer’s (also known as pyro-
Glu-Aβ(3/11–40) oligomers)(König et al., 2021). Both 

on-pathway precursor and off-pathway competitors can 
be acted upon by the oligomers during the oligomer to 
mature fibril conversion for Aβ42. Mostly composed 
of  residue Aβ peptide species, these fibrils have well-
known structures. The β-strands of  these firbils are 
oriented perpendicularly to the fibril axis, giving them 
a general appearance of  cross-shaped β structure. Two 



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hydrophobic β-sheet segments with an in-register 
orientation and parallel orientation are present in these 
fibrils, despite their unstructured N-terminus (Saha & 
Jana, 2022). In order to examine the biological activities 
of  Aβ oligomers and evaluate their physicochemical and 
structural characteristics, various techniques have been 
devised to produce oligomers that are relatively stable and 
do not easily transform into amyloid fibrils. Aβ oligomers 
that are frequently employed in the examination of  animal 
and cellular models of  Alzheimer’s disease are Aβ-derived 
diffusible ligands, or ADDLs (Jang et al., 2023). The toxic 
conformer of  Aβ42, with a turn at positions 22/23, 
and the less toxic conformer, with a turn at positions 
25/26, were identified (Figure 3A) through systematic 
proline replacement and analyses using solid-state nuclear 
magnetic resonance (NMR) spectroscopy and electron 
spin resonance (ESR) to gather information on the 
secondary structure of  Aβ42 oligomers and fibrils. The 
turn at positions 22/23 is one of  the important secondary 
structures of  Aβ42 for cytotoxicity and aggregative ability, 
as was previously mentioned. We performed cross-linking 
of  the residues located at Aβ42 positions 21/24, 19/26, 
17/28, 15/30, and 13/32. An intramolecular disulfide 
bond at positions 17/28 is present in the Aβ42 analogue 
(Figure 3) (Matsushima et al., 2022).

Mixtures of  diverse species, varying in size from tiny 
to large, make up AβOs; however, it is still unclear 
which species are the most toxic (Araki, 2023). Our 
findings, along with numerous other in vitro and in vivo 
investigations, corroborate the notion that AβOs cause a 
range of  pathological changes, such as oxidative stress, 
mitochondrial dysfunction, synaptic deficits, apoptosis, 
aberrant tau alterations, and cognitive impairments (Araki 
& Kametani, 2022) Aβ oligomers may be involved in AD 
pathology in a number of  ways, such as neuronal toxicity 
and excitotoxicity caused by constriction of  brain blood 
vessels due to increased calcium levels. AD can start in vivo 
and in vitro when small soluble Aβ1-42 oligomers cause 
neurotoxicity. For this reason, it is currently thought that 
Aβ oligomers are more neurotoxic and disease-relevant 
than Aβ fibrils (Matuszyk et al., 2021). When AβOs 
binds to different receptors on the surface of  neurons, 
it can interfere with signaling pathways and cause cells 
to die. AβOs recognizes more than 20 receptors, such 
as β7nAChR, p75NTR, PrPc, glutamate receptors, and 
β2-AR. APP intracellular domain (AICD) production is 
decreased and β-secretase activity is inhibited by PrPc, 
an important protein that regulates Aβ metabolism in 
vivo under normal physiological conditions. Aβos, on the 
other hand, binds to PrPc and interferes with its normal 
physiological functions in AD brains (Huang & Liu, 2020). 
The majority of  scientists believe that Aβ oligomers cause 
synaptotoxicity by activating metabotropic glutamate 
receptor type 5 (mGluR5) and stimulating three kinases 
that inhibit LTP: c-Jun N-terminal protein kinase 
1, JNK1; cyclin-dependent kinase 5, Cdk5; and p38 
mitogen-activated protein kinase, p38 MAPK (Diociaiuti 
et al., 2021). The species most closely linked to the 
pathophysiology of  AD are soluble Aβ oligomers, which 
can be found in APP transgenic mice, AD patients, vitro, 
and in vivo in a wide variety of  forms. These diverse Aβ 
oligomer types show their neurotoxic effects in AD via 
multiple distinct mechanisms (Madhu & Mukhopadhyay, 
2021). The toxic influence of  AβOs has been extensively 
studied in transgenic animal models, AD brain tissues, and 
cell cultures. Numerous studies have shown that amyloid 
oligomers of  different origins can cause alterations in 
neurons. AβOs isolated from the brains of  AD patients or 
animal models of  the disease, as well as synthetic peptides 
or Aβ species secreted in cultured cells (Mroczko et al., 
2017). In summary, AβOs have been observed to trigger 
tau pathology, axonal transport impairment, loss of  
neuronal polarity, oxidative stress, endoplasmic reticulum 
(ER) stress, deterioration of  synapses, insulin resistance, 
neuroinflammation, cholinergic impairment, loss of  
trophic factors, epigenetic modifications, ectopic mitosis, 
and selective death of  nerve cells (Cline et al., 2018).
Chemical regulation of  amyloid-β oligomerization
Alzheimer’s disease and related illnesses are characterized 
by a pathogenic process called amyloid-beta aggregation. 
in order to develop effective treatments (Cline et al., 2018). 
Understanding how this aggregation is made is crucial. 
Treatment options include GAL-201, which is thought 

Figure 3: (A) Structure of  toxic and less toxic conformers 
with a turn at positions 22/23 and 25/26, respectively.20 
(B) Structure of  cross-linked Aβ42 analogues (1–6). 
Adopted from Ref  (Matsushima et al., 2022)

Role in Alzheimer’s Pathology
It is widely acknowledged that AβOs are important 
players in the pathogenetic mechanisms of  AD because 
of  their capacity to cause neurotoxicity, synaptotoxicity, 
and neuroinflammation, and because these effects can 
explain the neuropathological characteristics of  AD. 



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to bind preferentially to mis-folded Aβ1-42 monomers. 
This high-affinity binding prevents larger aggregates and 
harmful oligomers from forming by interfering with the 
aggregation process. Through its ability to inhibit Aβ 
aggregation, GAL-201 may be able to prevent or slow 
the onset of  amyloid-beta-related neurodegenerative 
diseases, such as Alzheimer’s (Russ et al., 2022). There are 
now multiple strategies to combat the Alzheimer’s-related 
Aβ assemblies (Fish et al., 2019). Immunotherapeutic 
vaccinations, antibodies, peptides, and nanoparticles are 
a few of  the tactics. Many compounds, such as Congo 
red, LPFFD, myricetin, melatonin, 9,10-anthraquinone, 
trehalose, Thioflavin T, N-methylated peptides, 
polyphenol EGCG, ibuprofen, naproxen, morin, and 
particular polyphenolic compounds, have shown promise 
in blocking Aβ aggregation and upsetting beta sheet 
structures (Grasso & Danani, 2020). Plants like berries 
and grapes contain a polyphenolic flavonoid called 
myricetin, which has a variety of  biological activities 
such as antibacterial, anti-inflammatory, and antioxidant 
properties. Inhibition of  Aβ oligomerization by myricetin 
has also been demonstrated (Araki & Kametani, 2022). 
Anti-Aβ monoclonal antibodies have the ability to stop 
Aβ monomers from forming fibrillar aggregates in vitro 
and to change fibrillar aggregates into an amorphous 
form. It’s interesting to note that these mechanisms’ 
effectiveness is influenced by antibody concentration 
(Mantile & Prisco, 2020) . There have been reports of  
certain anti-Aβ antibodies binding directly to Aβ, which 
either dissolve Aβ aggregates in vitro or prevents Aβ 
from oligomerizing and forming fibrils. Particular Aβ 
antibodies with specific conformations target pre-existing 
brain plaques and cause direct in vivo disintegration. 

According to these results, Aβ aggregation may be 
impacted by the direct interaction of  anti-Aβ antibodies 
with Aβ in both vitro and in vivo settings (Liu et al., 2025). 
A phase III clinical trial for four monoclonal anti-Aβ 
antibodies—adecaluzumab, BAN2401, gantenerumab, 
and solanezumab—has begun, according to a recent 
study. Aducanumab is a human IgG1 antibody that targets 
only soluble oligomers and insoluble fibrils of  Aβ. It was 
chosen through memory B cell screening in healthy elderly 
individuals (Panza et al., 2025). The FDA has recently 
approved it as an immunotherapy for AD. Aducanumab 
(BIIB037) is a monoclonal antibody of  human IgG1 that 
forms an extended conformation with the N terminus of  
Aβ. It targets aggregates of  Aβ, including insoluble fibrils 
and soluble oligomers (Song et al., 2022). Using molecular 
docking, the virtual peptide P21 is able to effectively 
inhibit the aggregation of  Aβ1-42 proteins, thereby 
decreasing neurotoxicity (Wu et al., 2023). Two classes 
of  poly-phenols inhibit the aggregation of  Aβ in distinct 
ways. On the one hand, flavonoids led to the formation 
of  spherical, unstructured aggregates and completely 
inhibited the fibrillation of  Aβ monomers. Conversely, 
stilbenes suppressed Aβ aggregation, although to a 
much smaller degree. Remarkably, the common stilbene 
resveratrol speed up the production of  Aβ fibrils (Phan et 
al., 2019). Metal ions have been shown to either accelerate 
or slow down Aβ aggregation based on the total metal ion 
concentration and metal:Aβ ratio, as has been covered in 
multiple review articles. While it has been demonstrated 
that Cu (II), Zn(II), and Ag(I) slow down Aβ fibrillization 
at low metal ion concentrations, Aβ aggregation can 
be stimulated at high concentrations, leading to the 
formation of  amorphous aggregates.

Figure 4: Model for mechanism of  action of  metal ion-modulated Aβ self-assembly

Transition-metal ions, in particular referring to Cu (II), 
Zn(II), and Ag(I) ions, specifically prevent fibril-end 
elongation events by forming a seemingly aggregation-
inert metal-bound Aβ complex. Inhibition of  fibril 
elongation predicts an enhanced rate of  oligomer 
generation. At high metal ion concentration, other 
aggregation processes dominate, and amorphous 
aggregates are formed. (b) An energy diagram shows 
the concentration-dependent formation of  Aβ fibrils 
and amorphous Aβ aggregates, where an increased 
concentration of  Aβ generally enhances aggregation 

and the energy barrier toward amorphous aggregate 
formation is determined by the metal ion concentration. 
Copy from ref  (Abelein, 2023).
Metal ions, particularly Zn2+ and Cu2+, have a strong 
affinity for binding to Aβ, which can facilitate Aβ 
nucleation and aggregation (Rana & Sharma, 2019). 
According to a recent study, quinoline-derived half-
curcumin dioxaborine (Q-OB) was made in order to 
identify the early stage of  AD by detecting the oligomeric 
Aβ1-42 over monomer and filaments in the complex Aβ 
self-assembly cascade. In AD transgenic mice, Q-OB 



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demonstrated exceptional blood-brain barrier (BBB) 
penetrability and in vivo imaging of  Aβ (An et al., 2024). 
The studies of  anti-Aβ 3D6 antibody is said to stop 
the development of  new Aβ plaques in the brain, but it 
doesn’t eliminate those that already exist. Additionally, 
3D6 inhibited the aggregation of  Aβ (Amano et al., 2023). 
The relationships between the Aβ peptide and the main 
Aβ aggregation inhibitors, geraniin (1), gallic acid (2), and 
corilagin (5), were investigated using STD NMR spectra. 
This study implies that smaller soluble Aβ aggregates are 
inhibited by corilagin (5), whereas larger insoluble Aβ 
aggregates are inhibited by gallic acid (2). Corilagin (5) 
only interacts with soluble Aβ, as demonstrated by this as 
well (Kubo et al., 2022). Certain classes, like polyphenols 
and tetracyclines, can prevent the aggregation of  various 
unrelated amyloidogenic proteins, like islet amyloid 
polypeptide (IAPP), which is linked to type-2 diabetes, 
and α-synuclein, which is linked to Parkinson’s disease. 
It’s likely that their mechanisms of  action are partially 
overlapped (Martinez Pomier et al., 2020). Many in vitro 
and in vivo investigations have demonstrated the potential 
of  a variety of  natural compounds as therapeutic agents 
against the progression of  AD however, pre-clinical 
and clinical studies have only demonstrated the efficacy 
of  a small subset of  these compounds (Andrade et al., 
2019). After being extracted from red maples, ginsenalin 
A (GA) can target Aβ42 fibrillogenesis through a variety 
of  mechanisms. Specifically, GA can bind to monomers 
at the early nucleation phase, preventing Aβ–Aβ 
associations, and at the later growth phase. According to 
toxicity tests on SH-SY5Y cells, pre-incubation of  Aβ42 

solution with GA results in oligomers that do not interact 
or disturb the integrity of  cellular membranes (Pagano et 
al., 2020). Further evidence suggests that the antioxidant 
ferrulic acid (FA), which is found in plant cell walls, may 
inhibit the aggregation of  Aβ (Thapliyal et al., 2021). The 
biomolecular targets linked to Alzheimer’s disease (AD) 
include the NMDA receptor, Aβ aggregation, AChE, and 
monoamine oxidase (MAO) (Uddin et al., 2020). (Figure 5) 
shows how harmine and its derivatives bind to numerous 
targets. Harmine treatments decrease scopolamine-
induced cognitive impairment in mice and enhance 
spatial learning, memory in transgenic mice, short-term 
memory in aged rats, and all of  these outcomes. This 
illustrates how harmine targets different aspects of  the 
disease and has the potential to be a multimodal treatment 
for Alzheimer’s (Du et al., 2023). Study investigated the 
potential therapeutic effects of  GnRb1, SA, and DMyr on 
Aβ aggregation in AD. Our study suggests that since SA, 
GnRb1, and DMyr target Aβ aggregation, they might be 
appealing treatment options for AD based on the amyloid 
hypothesis (Sharari et al., 2023). By significantly binding 
to Aβ oligomers and monomers, the nanoparticles (NP@
SiO2@F-SLOH) reduce Aβ aggregation, as confirmed 
by the ThT fluorescence experiment. This suggests the 
potential for Alzheimer’s disease (AD) treatment. Aβ 
species ranging from Aβ42 monomers and oligomers to 
Gd3+-based NPs with F-SLOH surface functionalization 
lessen neurotoxicity as well. Additionally, the NPs 
effectively stop Aβ species from generating reactive 
oxygen species (ROS), indicating that AD treatments may 
be possible with them (Wang et al., 2020).

Figure 5: Chemical structures of  harmine and its derivatives. Copy from ref  (Du et al., 2023)

Stabilization of  Amyloid-β Oligomers
A number of  tiny compounds have been demonstrated 
to be useful anti-aggregating agents in the treatment of  
Alzheimer’s disease, including curcumin, resveratrol, 
ellagic acid, meric decapeptide rk10, and epigallocatechin-
3-gallate (EGCG) (Mohammed et al., 2023). The active 
polyphenol found in green tea, called epigallocatechin-3-
gallate (EGCG), has drawn a lot of  interest because of  its 

potential for health benefits, which include anti-oxidation, 
radical scavenging, metal chelating, anti-carcinogen, anti-
apoptosis, and anti-inflammatory qualities (Mokra et 
al., 2022). EGCG activates the proteolytic pathway of  
nonamyloidogenic α-secretase, which inhibits the aging 
process of  the brain and lowers Aβ levels, according to 
several studies (Bao et al., 2020). Apart from its potential 
to prevent the creation of  harmful prefibrillar oligomers, 



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EGCG has also been proposed as a possible remodeler 
of  preexisting amyloid fibrils. Since EGCG is unstable 
and oxidizes quickly to produce a range of  products, most 
research is done at physiological pH (Sternke-Hoffmann 
et al., 2020). Research has demonstrated that polyphenols 
can either stop Aβ oligomerization from happening or 
restructure and stabilize Aβ oligomers into forms that 
are safe. To produce unstructured Aβ oligomers, EGCG 
inhibits Aβ fibrillogenesis. Smaller, more amorphous, 

nontoxic protein aggregates are assembled from freshly 
formed oligomers with its assistance (El Gaamouch et 
al., 2022). Catecholamine neurotransmitters have the 
ability to maintain Aβ in its oligomeric state, according 
to studies. Indeed, Aβ oligomer stabilization may involve 
the cooperation of  NE and DA. An elevated oligomer 
concentration is indicated by the aggregated Aβ, which 
is significantly blurred when NE and DA are present 
(Allnutt & Matera, 2023).

Figure 6: Structures of  neurotransmitters examined for stabilization of  Aβ oligomers.
Source: Adopted from (Allnutt & Matera, 2023)

An antioxidant, anti-inflammatory, and anticancer 
polyphenolic compound is curcumin. Its low bioavailability 
restricts efficacy despite its possible advantages in 
Alzheimer’s disease (AD) models (Momma et al., 2023). 
Enhancing bioavailability and brain translocation, GT863, 
a derivative of  curcumin, was synthesized. Together with 

dual stabilization of  Aβ and tau aggregation, in vivo 
studies showed that GT863 could ameliorate cognitive 
impairment in an AD mouse model. It would seem from 
this that GT863 is a good candidate for more study in the 
treatment of  AD.

Figure 7: Structures of  GT863 and curcumin.
Source: Adopted from ref  (Zhou et al., 2022)

Few compounds that can disassemble pre-formed 
oligomers have progressed to the point of  clinical trials, 
despite the fact that a large number of  Aβ aggregation 
inhibitors have been discovered in vitro. Trimiprosate, 
also known as 3-amino-1-propanesulfonic acid; 
AlzhemedTM), has been shown to bind preferentially 
to pre-fibrillar (monomeric and oligomeric) forms of  
Antibody, thereby preventing their conversion into 
higher-order oligomers and fibrils (Ono & Tsuji, 2020). 
Moreover, metal ions control Aβ polymorphism, stability, 
and aggregation. Based on our simulations, the stabilizing 
effect is dependent on the size of  the fibrillar oligomer 
and the type of  alkali ion. Studies looked at how fibrillar 
Aβ oligomers of  different sizes were affected by the three 
alkali metal ions Li+, Na+, and K+ (Huraskin & Horn, 
2019). According to recent research, small molecules 
with anti-oxidative properties, the majority of  which 
come from natural sources, can lessen the neurotoxicity 
of  AβOs (Araki & Kametani, 2022). Aβ42 aggregates are 

more toxic than the more prevalent Aβ40 because Aβ42 
peptides can form three-stranded motifs, which enable 
them to assemble into poreforming aggregates (ring- or 
barrel-shaped), and the brain environment—specifically, 
the presence of  fatty acids—enhances the formation of  
these aggregates. We discover that lauric acid stabilizes 
these aggregates (Khatua et al., 2021).

Degradation of  Amyloid-β Oligomers 
The degradation of  Aβ in the brains of  AD patients is a 
crucial area of  study to help understand the underlying 
mechanism of  Aβ degradation and to shed light on the 
disease’s pathogenesis (Zhang et al., 2020). Degrading 
the levels of  accumulated Aβ aggregates and inhibiting 
Aβ aggregation are therefore important, and doing so 
has become essential for the potential application as an 
appealing therapeutic and preventive strategy for the 
treatment of  AD (Cheng et al., 2020). Furthermore, there 
are still few ways to assess the degree of  Aβ degradation. 



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Circular dichroism (CD) and the thioflavin-T (ThT) 
fluorescence assay are frequently used to look into how 
the β-sheet structure in Aβ aggregates is being destroyed 
(Gao et al., 2022). By tracking the decrease in Aβ 
concentration over time, the Aβ degradation has also been 
identified using sandwich enzyme-linked immunosorbent 
assay (ELISA) and western blot techniques (Rostami et al., 
2021). These methods do, however, still have a number of  
drawbacks, including a high potential for false positive/
negative results or results that are subject to subjectivity, 
the need for careful handling and accuracy at every stage, 
and high individual costs associated with the preparation 
of  antibodies and culture media. To measure the enzymatic 
breakdown of  Aβ, some peptide mapping investigations 
are carried out, which involve gathering fractions from 
liquid chromatography (LC) and then using off-line 
mass spectrometry (MS) (Moracci et al., 2021). Studies 
conducted recently indicate that nattokinase (NK) may 
play a part in the treatment of  diseases related to Aβ42 
aggregates, like AD, as it can gradually break down Aβ42 
aggregates at neutral pH and body temperature (Chen et 
al., 2018). After then, Aβ is eliminated by non-proteolytic 
or enzyme-mediated mechanisms. There are currently 
about 20 different proteases known as Aβ degrading 
enzymes (ADEs), which mediate the proteolytic 
degradation of  Aβ (Sikanyika et al., 2019). Aβ clearance 
can be categorized into two main groups: enzymatic and 
non-enzymatic. Enzymatic clearance involves the action 
of  Aβ-degrading enzymes (ADEs), which function as 
proteases to break down Aβ peptides into smaller, less 
harmful forms. While most degradation is believed to 
occur within the brain, clearance may also happen in 
other areas where Aβ is found after being cleared from 
the brain. A variety of  ADEs have been found from 
different classes of  proteases, including metallo-serine, 
aspartyl, cysteine, and threonine proteases (see Table 1). 
Many of  these proteases have the ability to break down 
multiple peptide substrates in various tissue locations 
(Żukowska et al., 2023). Neprilysin (NEP) and insulin-

degrading enzyme (IDE) are the most well-characterized 
AβDPs. They are both zinc-metalloendopeptidases that 
are primarily involved in the breakdown of  monomeric 
species, though neprilysin has also been reported to 
hydrolyze Aβ oligomers (de Dios et al., 2019). Insulin-
degrading enzyme (IDE) is a widely distributed Zn2+-
metalloprotease present in various human tissues and 
organs. Extensive research has suggested a strong 
link between IDE and Alzheimer’s disease (AD). 
Clinical and in vivo investigations have consistently 
shown that reduced IDE levels in the brain of  AD 
patients contribute to the advancement of  the disease 
(Abramov-Harpaz & Miller, 2022). Enzymes such as 
endothelinconverting enzyme, neprilysin (NEP), insulin-
degrading enzyme (IDE), and matrix metalloproteinase9 
show a decrease in the accumulation of  Aβ. While matrix 
metalloproteinase-9 enzyme was discovered to degrade 
both soluble Aβ species and Abfibers, IDE and NEP 
are reported to be able to remove soluble Aβ (Sahoo et 
al., 2021). Zinc metalloproteases known as endothelin-
converting enzymes, or ECEs, are made by astrocytes, 
endothelial cells, and neurons. ECE-1 and ECE-2 exhibit 
59% homology and comparable catalytic activities; 
however, these activities differ in terms of  their ideal pH, 
with ECE-1 activity requiring a physiological pH and 
ECE-2 activity requiring an acidic pH (5.5). They were 
proposed to be involved in the breakdown of  monomeric 
Aβ before its secretion, and they mainly break down 
intracellular Aβ (Loeffler, 2023). One important protease 
that breaks down fibrin in blood clots is called plismin 
(Plm). Plm, along with tissue-type plasminogen activator 
(tPA) and urokinase-type plasminogen activator (uPA), 
is one of  the three components of  plasmin-based 
thrombolysis (Yang et al., 2020). Plm is derived from its 
inactive form, plasminogen (Plg). Amyloid-beta (Aβ) has 
been shown to be directly degraded by Plm, which also 
targets its monomeric and fibrillar forms while lessening 
their toxicity. This implies that Plm may have a part in 
resolving Aβ-related problems (Loeffler, 2023).

Table 1: Presents a list of  enzymes that have shown the ability to degrade Aβ in laboratory studies. However, 
the complete characterization of  each protein’s biological significance is still incomplete. Neprilysin-2 (NEP-2) is 
referred to by various names in the literature, including SEP, NL1, MMEL1, and NE_PLP.
Aβ degrading enzymes Aβ degrading enzymes
Neprilysin (NEP) Matrix metalloprotease-14 (MMP-14)
Endothelin-converting enzyme-1 (ECE-1) Myelin basic protein (MBP)
Endothelin-converting enzyme-2 (ECE-2) Plasmin
Angiotensin-1 converting enzyme (ACE) Aminopeptidase A
Angiotensin converting enzyme-2 (ACE-2) Mitochondrial presequence protease (PreP)
Insulin-degrading enzyme (IDE) Acyl peptide hydrolase (APEH)
Matrix metalloproteinase-2 (MMP-2) Cathepsin B
Matrix metalloproteinase-9 (MMP-9) Cathepsin D
Beta secretase 1 (BACE 1) Beta secretase 2 (BACE 2)
26S proteasome.

Source: Adopted from (Żukowska et al., 2023)



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CONCLUSION
It is concluded that Amyloid-beta (Aβ) oligomers have 
important role in Alzheimer’s disease (AD) pathogenesis, 
neuroinflammation and cognitive decline through 
liquid-liquid phase separation (LLPS) and dynamic 
aggregation. This study highlighted progress in targeting 
Aβ oligomers with metal complexes, small molecules and 
immunotherapies, which make stable nontoxic forms 
and control aggregation, or regulate degradation. Main 
challenges include the heterogeneity in structure and the 
desire for blood-brain barrier-permeable therapeutics. 
Innovative strategies, such as Aβ-degrading enzymes 
and LLPS inhibitors, offer breakthrough pathways 
for early intervention. Future studies should prefer 
in vivo validation for phase-separation modulators, 
microstructural characterization of  oligomers and 
biomarkers for early detection. By combining chemical 
biology and neurotherapeutics, this field proceeds closer 
to disease-modifying treatments that degrade Aβ toxicity 
at its point source, offering hope for overstaying AD 
progression.

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