Biomedicine & Pharmacotherapy 144 (2021) 112250

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Mechanistic role of boswellic acids in Alzheimer’s disease: Emphasis on

anti-inflammatory properties
Aisha Siddiqui a, Zahoor Shah b, Rao Nargis Jahan c, Iekhsan Othman d, Yatinesh Kumari a, *
a
Neurological disorder and aging research group (NDA), Microbiome and Bioresource Research Strength (MBRS), Jeffrey Cheah School of Medicine and Health Sciences,
Monash University Malaysia, 47500, Selangor, Malaysia
b
Department of Medicinal and Biological Chemistry, University of Toledo, 3000 Arlington Avenue, Toledo 43614, OH, USA
c
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard University, New Delhi 110062, India
d
Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Selangor, Malaysia

A R T I C L E I N F O A B S T R A C T

Keywords: The resin/gum of Boswellia species belonging to the family of Burseraceae is a naturally occurring mixture of
Boswellic acids bioactive compounds, which was traditionally used as a folk medicine to treat conditions like chronic inflam­
Neuroinflammation mation. Several research studies have also explored its’ therapeutic potential against multiple neurodegenerative
Inflammatory mediators
diseases such as Alzheimer’s disease (AD). The main chemical constituents of this gum include boswellic acids
Alzheimer’s disease
Signalling pathways
(BAs) like 3-O-acetyl-11-keto-β boswellic acid (AKBA) that possess potent anti-inflammatory and neuroprotective
properties in AD. It is also involved in inhibiting the acetylcholinesterase (AChE) activity in the cholinergic
pathway and improve choline levels as well as its binding with nicotinic receptors to produce anti-inflammatory
effects. Multiple shreds of evidence have demonstrated that BAs modulate key molecular targets and signalling
pathways like 5-lipoxygenase/cyclooxygenase, Nrf2, NF-kB, cholinergic, amyloid-beta (Aβ), and neurofibrillary
tangles formation (NFTs) that are involved in AD progression. The present review focuses on the possible
mechanistic therapeutic role of BAs in modulating the 5-LOX/COX pathway in arachidonic acid metabolism,
activating Nrf2 through binding of ARE, inhibiting NF-kB and AChE activity. In addition, an inhibition of am­
yloid plaques (Aβ) and neurofibrillary tangles (NFTs) induced neurotoxicity and neuroinflammation in AD by
BAs is also discussed in this review. We have also highlighted that BAs possess beneficial effects in AD by tar­
geting multiple molecular pathways and makes it an emerging drug candidate for treating neurodegenerative
diseases.

1. Introduction molecules resulting in altered lipid metabolism [4]. In addition, previ­

Alzheimer’s disease (AD) is described as a neurological disorder
primarily affecting the elderly population marked by dementia,
impaired cognition, and changes in behaviour. According to Alzheimer’s
Disease International (2019) report it is estimated that approximately 50
million of the population are suffering from dementia until the present
day, which may increase up to 152 million by 2050 [1].
Hallmarks of AD include Aβ senile plaque formation and neurofi­
brillary tangle (NFTs) accumulation in the brain [2]. Soluble Aβ plaques
develop shortly after NFTs formation that triggers defects in synaptic
functions, mitochondria dysfunction and increases the release of reac­
tive oxygen species (ROS), contributing to oxidative stress [3]. More­
over, additional signs of AD include excessive production of lipid
ously formed senile plaques trigger elevated pro-inflammatory media­
tors like chemokines, cytokines, interleukins (ILs) that potentiate AD
progression. Moreover, the twin role of chemokine engagement as anti
and pro-inflammatory mediators is well understood, but clinically it
needs to look upon further in AD progression [5,6]. These signalling
molecules regulate central nervous system (CNS) functions and patho­
genesis of neurological diseases like AD through different cascades that
contribute to inflammation- induced AD.
The 1980 s report suggests that immune cells and proteins occupy the
area close to β-amyloid plaques [7,8]. Moving to the 1990 s, many
observational studies and epidemiological data revealed that the
anti-inflammatory therapies for diseases like arthritis had shown ther­
apeutic efficacy against AD development. These patients were long-term

* Corresponding author.
E-mail address: Yatinesh.kumari@monash.edu (Y. Kumari).

https://doi.org/10.1016/j.biopha.2021.112250
Received 19 July 2021; Received in revised form 17 September 2021; Accepted 26 September 2021
Available online 1 October 2021
0753-3322/© 2021 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Siddiqui et al.
NSAIDS consumers and showed a 50% lower risk of AD development
[9–12]. These reports persuade to utilize transgenic AD animal models
to observe the mechanism of NSAIDS involved in AD pathologies [13].
Later, clinical trials using NSAIDS showed results but without objective
evidence of effectiveness [14]. Such previous studies support the role of
neuroinflammatory pathways involved in developing AD. Moreover,
neuroinflammation results from more than one risk factor associated
with AD pathologies that play to boost the disease severity by worsening
tau and β-amyloid pathologies [15,16]. During inflammation NFTs and
Aβ plaques accumulate together with astrocytes, microglia, and other
immune cells in the brain [17]. Meanwhile, genome-wide association
studies (GWAS) have explained a strong correlation between immune
cells and AD development [18–20]. This investigation demonstrated
that Aβ plaque and tau formation are stimulated by pro-inflammatory
mediators [21,22]. During the chronic neuroinflammation, activated
immune cells like microglia release pro-inflammatory cytokines, ROS,
and nitric oxide and promote tau hyperphosphorylation, which con­
tributes to AD pathology [23]. However, activated immune cells
through phagocytosis also stimulate the Aβ plaque clearance [24]. A
study by Goldgaber et al. in 1989 had analysed the brain samples of dead
patients who suffered from a recent head injury and demonstrated
elevated Aβ aggregates. It is evident that increased IL-1 expression is
culpable for augmented amyloid precursor protein (APP) and Aβ pro­
duction [25,26]. Improved IL-1β levels also increase other cytokines
production, in parallel with IL-6, which activates a cyclin dependant
kinase enzyme CDK5 for tau hyperphosphorylation [27]. In AD neuro­
inflammation appears to function as a preliminary contributing factor in
exaggerating tau and Aβ load; however, it is still debatable whether
inflammation is a driving factor for AD or vice-versa [28].
At present, only five FDA-approved drugs for AD are in use, including
4 cholinesterase inhibitors i.e., tacrine, donepezil, rivastigmine and
galantamine and one NMDA receptor antagonist memantine [29]. These
drugs are more of a palliative therapy instead of a curative. [30].
However, in June 2021 the FDA approved monoclonal antibody, adu­
canumab, an IgG1 anti–amyloid-β (Aβ) antibody has shown an emerging
scope against AD progression [31]. In this regard, a study conducted by
Jeff Sevigny and colleagues has demonstrated that aducanumab suc­
cessfully cleared Aβ aggregates in a dose-dependent manner in the ro­
dent model of AD. Additionally, this therapeutic agent has been found to
reduce Aβ plaques and cognitive decline in AD patients [32].
The limited treatment options against AD, have prompted the re­
searchers to explore potent pharmacological agents/adjuvants with
broad biological activity and fewer side effects to treat neurodegenera­
tive diseases. In view of this, bioactive compounds from natural sources
have shown potential therapeutic benefits against various neurological
disorders, including AD [33]. One such biologically active compound is
boswellic acid (BA) which is procured from the oleo gum resin of the
various Boswellia species. However, few species such as Boswellia ser­
rata, Boswellia carteri, Boswellia sacra have been investigated to possess
therapeutic potential for chronic diseases like cancer, arthritis, inflam­
matory disease, Parkinson’s disease and Alzheimer’s disease. There is
still a broad scope to investigate the role of a bioactive component of
boswellic acids obtained from various Boswellia species [34]. In the
present review, we discussed the individual role as well as the crosstalk
of Nrf2, NF-kB cascades that majorly contribute to neuroinflammation,
neurotoxicity, and AD. Additionally, we have highlighted the patho­
genesis of AD via the cholinergic pathway, Aβ and neurofibrillary tan­
gles formation that plays a crucial role in neuroinflammation,
neurotoxicity and apoptosis. Moreover, the role of BA in modulating
these pathways and molecular targets has also taken into consideration.
2. Boswellic Acids (BAs)
Genus Boswellia belongs to the family Burseraceae, and it was tradi­
tionally used as a medicine. Phytochemical constituents of this family
are pharmacologically active. Its gum/resin is one of the primary and
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Biomedicine & Pharmacotherapy 144 (2021) 112250
most popular ingredients used in alternative and complementary med­
icine systems, which has shown therapeutic potential against gastroin­
testinal, inflammatory, microbial, and hormonal diseases [35].
Conventionally, the gum resin has also been used for cosmetic products,
different adhesive, coating substances, the essence employed in tradi­
tional ceremonies.
Approximately 25 species of Boswellia are dispersed in the moun­
tains of India, Arabia, and Northeast Africa. The resins in India are
famous as salai guggul, which consists of volatile oils, mucus, and resin
acids [35,36]. These resins are also comprised of penta and tetracyclic
triterpenes. However, the percentage of the constituents differs from
species to species [Table 1] [37].
2.1. Penta and tetracyclic triterpenes
Particularly 12 kinds of pentacyclic triterpenes have been identified
in Boswellia extract samples shown in [Table 2] [38]. Out of these
samples, two are found to be most active i.e., 11-Keto-β-boswellic acid
(KBA) and Acetyl-11-keto-β-boswellic acid (AKBA).
There are three tetracyclic triterpenes which are 3-acetoxytirucallic
Acid, 3-oxotirucallic acid and 3-hydroxytirucallic acid. Additional
components that are pharmacologically active are: lupeolic acid, acetyl-
lupeolic acid, betulinic acid, incensole acetate, incensole oxide, iso­
incensole oxide, isoincensole acetate [39].
2.2. Pharmacokinetics of BAs
Different boswellic acids (BAs) have shown therapeutic benefits
against neurodegenerative diseases, and inflammatory conditions, it is
important to emphasize the pharmacokinetics of BAs, as these properties
play a crucial role in drug development to achieve maximal efficacy in
vivo [41–43]. In this context, the concentration of different BAs (KBA,
AKBA, αBA, βBA, AαBA, AβBA) in rat brains were examined, and it has
been found that after 8 hrs of oral administration of Boswellia serrata
gum resin extract (240 mg/kg), the maximum levels of the above
mentioned BAs in the brain was found to be for βBA (1066.6 ng/g)
followed by αBA (485.1 ng/g), AβBA (163.7 ng/g), AαBA (43.0 ng/g),
AKBA (37.5 ng/g) and KBA (11.6 ng/g) [44]. Furthermore, another
study analysed the concentrations of the two most potent BAs i.e., KBA
and AKBA in rat brains, and their level was found to be 99 and 95 ng/g of
the brain, respectively. These concentrations of KBA and AKBA were
detected 3 h after peroral administration of 240 mg/kg of dry Boswellia
serrata to Wistar rats [45]. A recent study compared the concentration of
AKBA in rat brains after administration through the intranasal and
sublingual route. It has been observed that AKBA has efficiently abled to
cross the blood brain barrier (BBB) and the bioavailability of AKBA was
significantly higher in case of sublingual route when compared to
intranasal administration, as demonstrated by area under curves (AUCs)
analysis [46]. A human pharmacokinetic study was performed to mea­
sure the elimination half-life and plasma concentration of Boswellia
serrata extract (BSE). It has been noted that the elimination half-life of
the drug was about six hours and peak plasma levels of the drug reach 30
hrs after oral administration of 333 mg of BSE. This study also suggested
that the drug needs to be administered at a dosing interval of 6 hrs.
Moreover, the given dose was well tolerated by all the individuals and
no side effects were noted [47].
Table 1
Components of BA.
Boswellia serrata[37] Boswellia carteri Birdw[40]
Volatile oils 7.5–9–15 5–9
Mucus ~23 ≈ 12–20%
Pure Resin 55–57 ~66
A. Siddiqui et al.
Table 2
Types of pentacyclic triterpenes in Boswellia extract.
Constituents Percentage
α-Boswellic acid and β-Boswellic acid (β-BA) (α-BA) 10–21%[39]
Acetyl-α-boswellic acid (AαBA) and Acetyl-β-boswellic acid 0.05–6%[39]
(AβBA)
Acetyl-lupeolic acid and Lupeolic acid 1.10%, 2.61%[37,
38]
Acetyl-9–11-dehydro-α-boswellic acid and 11-Dehydro- 0.06%, 0.18%[37,
α-boswellic acid 38]
Acetyl-9–11-dehydro-β-boswellic acid and 9,11-Dehydro- 0.52%, 0.83%[37,
β-boswellic acid 38]
11-Keto-β-boswellic acid (KBA) 2.5–7.5%[39]
Acetyl-11-keto-β-boswellic acid (AKBA) 0.1–4%[38,39]
3. Signaling pathways and molecular targets modulated by BAs
Several studies indicated that BA possesses pharmacological prop­
erties like antiseptic, antineurotic, anxiolytic, analgesic [48]. In addi­
tion, it also showed potent anti-inflammatory activity against arthritis,
asthma, cerebral edema, and cancer [49,50]. The modification in
transduction signaling pathways gives rise to previously mentioned
chronic conditions that might impact population of all ages [51,52]. In
such diseases, BAs exerts its therapeutic benefits by modulating various
targets like growth factors, transcription factors, enzymes, kinases, and
receptors that may initiate apoptosis and finally arrest the cell cycle
[53]. It inhibits various pathways [54] associated with cell durability
[55], metastasis [56], proliferation [57].
The essential molecular mechanisms that have been investigated as
the biological targets of BAs are 5-Lipoxygenase (5-LOX), kinase enzyme
topoisomerase I, II, and Ikβ, human leukocyte elastase. Moreover, BAs
are known to regulate the Ca (2+/-) and mitogen-activated protein ki­
nases (MAPK) mechanisms, it is also involved in the pathways that are
essential for inflammation and tumor progression [58–60].
3.1. 5-Lipoxygenase (5-LOX)
The initial step of arachidonic acid cascade activation is to produce
inflammatory mediators like IFN-γ (interferon-γ), TNFα (tumor necrosis
factor α), ILs with the help of a membrane-linked enzyme phospholipase
A2 (PLA2). The two enzymes cyclooxygenase (COX-2) and 5-LOX are
responsible for the production of prostaglandins (PGs) and leukotrienes
(LTs), which finally precipitates to produce specific symptoms of
inflammation [37]. Moreover, they are the components of arachidonic
acid oxygenation that show an increased expression in aging brain
physiologies [61,62]. 5-LOX helps in the catalysis of arachidonic acid
into LTA4, which is further converted to Leukotriene B4 or C4 (LTB4,
LTC4) [63]. When deposited in the brain, these leukotrienes play a sig­
nificant role in altering the pathology of brain tissues [64,65]. Many
research studies support the participation of 5-LOX in AD development.
As evident from the comparative post-mortem study between healthy
and AD patient’s brains that expressed high levels of 5-LOX in the cortex
and hippocampal region of AD brains. However, no considerable dif­
ference was observed in both healthy and AD brain’s cerebellum (an
area devoid of AD pathogenesis) [66,67].
Furthermore, BA studies targeting inflammatory molecule 5-LOX
and COX enzymes came forward to explain the potential efficacy
against inflammation cascades. One such recent study by Mortiz Verhoff
et. al; in 2014 suggested that penta and tetracyclic triterpene acid from
the wellknown Boswellia species has shown to inhibit prostaglandin
synthesis by inhibiting the inflammatory action of COX enzymes [68].
Moreover, molecular docking studies have been helpful to understand
the pharmacological interaction of ligands/drugs with the active sites of
the receptors. Further investigation utilizing an automated molecular
docking approach to elucidate the binding of BAs was performed and
found a correlation between positive chemscore values for COX1 and
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Biomedicine & Pharmacotherapy 144 (2021) 112250
COX2. However, the binding affinity of BAs to COX1 was significantly
higher than COX2, indicating an increased sensitivity of COX1 for BAs as
noted in COX1 X-ray structures [69]. Another study revealed that BAs
possessed anti-inflammatory activity by inhibiting microsomal prosta­
glandin E2 synthase-1 (mPGES1), thus preventing the conversion of
PGH2 to PGE2. [70]. In vivo study in rodents showed that BA inhibited
prostaglandin E2 synthase-1 for the anti-inflammatory activity [70].
AKBA, in combination with COX inhibitors, prevented oxidative
stress-induced neuronal damage and cognitive impairment because of
the antioxidant, anti-inflammatory and anti-glutamatergic effects [62,
71]. In the LPS induced neuroinflammation rodent model, AKBA
significantly reduced pro-inflammatory mediators such as 5-LOX,
TNF-α, IL-6 levels and improve cognition [72]. The pathway of 5-LOX/­
COX and the role of BA based on the above studies is described in Fig. 1.
3.2. Nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway
Nrf2 is a member of cap ‘n’ collar family and is a chain of 605 amino
acid which is in cytoplasm during the inactivated stage and upon acti­
vation of various stimuli such as oxidative stress it translocates to the
nucleus to mediate its effects [73]. In basal conditions i.e., in cytoplasm
Nrf2 becomes the target of many ubiquitin molecules, whereas in the
nucleus, redox homeostasis is regulated by Nrf2 accumulation, which
carries out the normal antioxidant response element (ARE) associated
gene expression. Furthermore, Nrf2-ARE pathway in the cytoplasm is
governed by separation and deterioration of Nrf2 through Kelch Like
ECH Associated Protein 1 (KEAP1) binding [74]. ARE activators or stress
stimuli make conformational changes in KEAP1 which unbind Nrf2 and
allows it to translocate into the nucleus. Other processes like phos­
phorylation by AMP-activated protein kinase (AMPK), acetylation, and
protein kinase C (PKC) also stimulate Nrf2 and KEAP1 separation [74].
Nrf2 is known for regulating the redox homeostasis process which
involves activation of other pathways [75] consists of antioxidant and
anti-inflammatory molecules [76–80]. Nrf2 exerts its protective action
by regulating the function of molecules like heme oxygenase-1 (HO-1),
glutathione S-transferase (GST), superoxide dismutase (SOD), Nicotin­
amide adenine dinucleotide phosphate (NAD(P)H), malondialdehyde
(MDA), brain-derived neurotrophic factor (BDNF), and prevents degra­
dation of inhibitory kappa B alpha (IĸBα) thereby suppressing nuclear
factor kappa β (NF-kB) dependent pro-inflammatory molecules expres­
sion such as IL-6 [81]. As evident from a study in APPswe/PS1dE9 mice
treated chronically with AKBA showed antioxidant properties by
improving the levels of SOD and GSH in the hippocampus and cerebral
cortex regions when compared with the wild-type group. Similarly, such
a treatment also resulted in a decreased expressions of TNF-α, IL-1β, IL-6
and MDA in both regions of the brain. These findings strongly suggest
AKBA elicited Nrf2/HO-1/NF-kB-mediated antioxidant and
anti-inflammatory responses [82].
Downregulation of Nrf2 function increases the risk of cell damage by
ROS and pro-inflammatory molecules [83–86]. The possible underlying
neuroprotective mechanism of Nrf2 could be attributed to its
anti-inflammatory activity, as demonstrated by the downregulated
mRNA expression levels IL-6, inducible NO synthase, and TNF-α in mice
model of neuroinflammation [87]. Furthermore, ROS are known to
aggravate beta-site APP cleaving enzyme 1 (BACE1), which enhances
the generation of Aβ plaques [88]. The presence of Aβ lesions represents
chronic inflammation in AD brains [89]. Data from the previous study
on APP/PS1 mice suggest that disruption of Nrf2 cascades results in a
considerable rise in APP, Aβ1–40 and Aβ1–42 [90]. Moreover, a study by
Branca et al., explored that increase in amyloid plaques is faster in
APP/PS1/Nrf2− /− mice than APP/PS1 mice. However, the deficiency
of Nrf2 in APP/PS1 mice influences OS [91] and attenuation of Nrf2
associated pathways in APP/PS1 mice occurs during Aβ aggregation.
Particularly, Nrf2 upregulation in in-vitro prevents Aβ induced neuro­
toxicity [92].
This increased defense activity of Nrf2 against stimuli such as
A. Siddiqui et al.
Fig. 1. Represents the inhibition of 5–Lipoxygenase and cyclooxygenase by BA in AD pathogenesis. PLA2- phospholipase A2; IFN-γ-interferon-γ; IL-1/6; interleukin
1/6; 5-LOX- 5- Lipoxygenase; COX- cyclooxygenases; PGs- prostaglandins; Txs- thromboxanes; LTA4/B4/C4- leukotrienes; TNF-α- tumor necrosis factor α; BACE1-
beta-site APP cleaving enzyme 1; APP- amyloid precursor protein; Aβ- amyloid-beta; CDK5- cyclin dependant kinase enzyme; P- phosphorylation; AD- Alzheimer’s
disease; BA- boswellic acid.
oxidative stress and plaque accumulation occurs in response to inflam­
mation, injuries, and harmful substances. NF-κB also gets activated by
similar stimuli; therefore, Nrf2- NF-κB together work as a team to
equalize each other’s performance [74].
3.3. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
kB) signaling pathway
NF-kB pathway is characterized as a canonical and noncanonical
pathway that gets activated as a response to various stimuli. Canonical
cascade involves activation of stimuli like cytokines after recognising
the receptors such as Toll-like receptors (TLRs), IL-1 receptor (IL-1R),
tumor necrosis factor receptor (TNFR) and antigen receptors that stim­
ulate signaling pathways eventually activating inhibitory nuclear factor
kappa β kinase (IKKβ). Activation of IKKβ leads to the phosphorylation of
IĸB proteins which establish the platform for ubiquitination and pro­
teosomal degeneration, therefore, relocating the NF-kB dimers into the
nucleus, where binding to defined DNA sequences takes place via
transcription of targeted genes to regulate oxidative stress, inflamma­
tion, and apoptosis. Noncanonical pathway includes selected constitu­
ents of the cytokine group that is responsible for p100 phosphorylation
and p52/RelB complex formation by activating inhibitory nuclear factor
kappa α kinase (IKKα) [93,94].
The underlying inflammatory, pro-inflammatory, growth response
and stress genes are transcripted under NF- kB supervision [95]. Surely,
one of the important investigations of NF- kB role in aging and other
pathophysiologies is the regulated transcription of cytokines levels like
IL-1α/β, TNF-α and proteins like β2 microglobulin. Moreover, to
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Biomedicine & Pharmacotherapy 144 (2021) 112250
accelerate the recruitment and adhesion of immune cells at the in­
flammatory site, NF- kB improves chemokine and adhesion molecules
expression [96]. In AD, NF-kB regulates the BACE1 and APP expression
[97], leading to increased Aβ formation [98]. Another in vivo and in
vitro study showed that activated NF-kB effectuate β secretase levels in
neurons [99]. Recently, a study has demonstrated that AKBA at a dose of
5 mg/kg, when administered sublingually in a rodent model, has shown
a significant suppression of NF-kB signaling activity, as evident by
decreased NF-kBp65 expression, to exert the neuroprotective effects.
These investigations substantiate that NF-kB cascades could be playing a
significant role in AD development [46].
3.4. Crosstalk between NRF2 and NF- ĸB
Alzheimer’s disease is strongly associated with neuroinflammation
and neurodegeneration. Nrf2 and NF- kB are popularly determined as an
essential component of inflammatory cascades and therefore indicating
a promising approach for inflammation-derived AD therapy. These two
factors coordinate and balance oxidative stress and inflammation.
Various genetic and pharmacological research has shown important
crosstalk between Nrf2 and NF-kB pathways [100]. Nrf2 activation in­
creases the expression of HO-1 and prevents IκB degradation, which
inhibits NF-kB activation and ROS generation [101–103]. Likewise,
transcription mediated by NF-kB suppresses Nrf2 activation by
decreasing ARE genes and unoccupied CREB binding protein (CBP) by
fighting with Nrf2 for CBP thus suppressing Nrf2 activation [104,105].
A recent study by Chao Wei et.al., has shown the neuroprotective
role of AKBA through Nrf2 and NF-kB interplaying pathways. Chronic
A. Siddiqui et al. Biomedicine & Pharmacotherapy 144 (2021) 112250

administration of AKBA in APPswe/PS1dE9 mice brain has shown a
reduction in inflammatory mediators like TNF-α, IL-1β and IL-6. AKBA is
presumed to selectively inhibit NK- kB pathway and activate Nrf2/HO1
pathway. Moreover, AKBA treatment has shown improvement in syn­
aptic function through the recovery of synaptic integrity and plasticity,
ameliorating cognitive impairments due to reduced inflammation,
oxidative stress and Aß production [82]. Ding et al. in 2014 has reported
that BAs has shown neuroprotection by significantly reducing infarction
volume and apoptosis in the Sprague Dawley rat model of
Oxygen-glucose deprived ischemic injury induced by oxidative stress.
AKBA has shown enhanced Nrf2 binding to ARE. Therefore, this study
suggests that AKBA shows neuroprotective effects against ischaemic
injury via nuclear factor erythroid-2-related factor 2 (Nrf2)/heme
oxygenase-1 (HO-1) cascade activation [106,107]. As discussed previ­
ously, the role of Nrf2 and NF-kB in AD and the therapeutic potential of
BA in modulating the above pathways are illustrated in Fig. 2.
3.5. Cholinergic anti-inflammatory pathway
In AD, the decline in choline levels results in cortical dysfunction,
memory deficit, abnormal cerebral blood flow, task learning difficulty,
disrupts the sleep cycle and cortex development [108]. The dysfunction
in the acetyl choline pathway in AD takes place at different stages
involving reduced acetylcholinesterase (AChE) activity and choline
uptake, less acetylcholine (ACh) synthesis and its receptors (AChR). In
AD, AChE plays a role independent of choline which contributes to in­
flammatory responses [109–114], Aβ complex formation and
cytotoxicity mechanism [115,116].
Neurons after activation are dependent on choline for getting back to
their resting phase; therefore, choline is produced by the hydrolysis of
ACh in the presence of AChE [117]. The cholinergic anti-inflammatory
pathway involves the inhibition of TNF and other pro-inflammatory
cytokines release and control inflammation. This unique performance
is forced by the efferent vagus nerve, which is evolved from the dorsal
vagal nucleus within the medulla oblongata. Electrical stimulation of
vagus nerve (VNS) or guanyl hydrazone CNI-1493 communicates with
α7 subunit-consisting nicotinic receptors (α7nAchR). Activation of these
nicotinic receptors involves cholinergic transmission that eventually
suppresses TNF synthesis and systemic inflammation [118]. Further­
more, α7nAchR stimulation on macrophages suppresses
pro-inflammatory mediators, released by inhibiting NF-kB cascade
[119]. Additionally, the administration of nicotine in epithelial cells
decreases TNF-α, IL-6, and IL-1β expression regulated by α7nAchR and
NF-kB signaling pathway [120]. Moreover, in the previous study it has
been observed that AChE also aggravates Aβ formation and neurotox­
icity [121]. Therefore, many studies have been conducted to explore the
efficacy of BAs on the acetylcholinesterase pathway in AD. In a diseased
state, the AChE activity was found to be increased, which results in
decreased ACh levels leading to a loss in neuronal communication
[122]. Findings from a recent study suggested the reduced levels of ACh
were improved as well as elevated activity of AChE was reduced in
chemo-preventive and chemo-therapeutic groups of BA in the rodent
model of AD [123]. A possible pharmacodynamic activity that has been
concluded yet is that BAs can significantly reduce/inhibit AChE in serum

Fig. 2. Schematic representation of BA inhibiting the inflammatory mechanism in crosstalk between Nrf2 and NF-kB induced neurotoxicity and AD. ROS- reactive
oxygen species; Nrf2- Nuclear factor erythroid 2–related factor 2; Keap1- Kelch Like ECH Associated Protein 1; Ub- ubiquitination; AMPK- AMP-activated protein
kinase; PKC- protein kinase C; P- phosphorylation; A- acetylation; Ik-Bα-inhibitor of nuclear factor kappa B; NF-kB- Nuclear factor kappa-light-chain-enhancer of
activated B cells; ARE- antioxidant response element; HO-1- Haemeoxygenase 1; SOD- superoxide dismutase; GST- glutathione S-transferase; NADPH- nicotinamide
adenine dinucleotide phosphate; MDA malondialdehyde; BDNF- brain-derived neurotropic factor; BACE1- beta-site APP cleaving enzyme 1; APP- amyloid precursor
protein; Aβ- amyloid-beta; IL-1a/β - Interleukin 1a/β; IL-6- Interleukin 6; TNF-α- tumor necrosis factor α.

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A. Siddiqui et al. Biomedicine & Pharmacotherapy 144 (2021) 112250

against trimethyltin (TMT) induced neurotoxicity in a rodent model
[124]. Since TMT is a neurotoxic agent that causes an increase in AChE
levels leading to change in behaviour, learning and cognitive decline
[125,126]. Moreover, increasing the dose of BA in the same model has
shown promising results in improving neuronal health of the hippo­
campus and cortex region when observed in the Morris water maze test
[124]. As illustrated below in Fig. 3 is the summary of the above finding.
3.6. Amyloid-β and tau proteins deformities and microtubule organisation
The most highlighted proteins in AD are tau and Aβ [127], their
accumulation in AD brains is known to be a major hallmark [128]. Tau is
a microtubule-associated cytosolic protein (MAP) found in the axonal
length of the neuron [129]. This protein plays a crucial role in stabilizing
microtubules, maintaining DNA and overall neuronal health [130,131].
There are series of events that act as stimuli (chemical, physical or
infection) to initiate inflammation. Activation of microglial cells and
astrocytes deliver inflammatory mediators like nitric oxide (NO), TNF-α,
PGs, IL-6 and ROS. These agents work collectively to initiate neuro­
toxicity. One consequence is the disruption in ubiquitin-proteosome
cascade, which leads to the aggregation of proteins. These proteins, if
not cleared away then cells trigger neuroinflammation and apoptosis.
However, proteolysis by caspase induces tau cleavage; this further leads
to the accumulation of protein fragments which if not cleaned up by the
lysosomal or autophagy pathway then accumulation begins leading to
neurodegeneration [132]. Tau aggregation can also be initiated by
polyanions trigger charge compensation of the middle portion of the tau
chain; therefore, hyperphosphorylated tau begins to form NFTs intra­
cellularly which interferes in regular neuronal communication [133].
Moreover, in developed neurons, impaired axonal transport is generally
known to be a major factor for most of the neurodegenerative disorders
involving AD [134].
Microtubule stabilization is an essential measure of the normal
function of neurons. Defects in microtubule association have been
studied in AD. A study by Brandt and Bacota states that adjusting the
microtubule dynamics can be considered a promising approach for AD
drugs [135]. On the other hand, Aβ peptide is known to form plaques
extracellularly [136]. These peptides at the required physiological
concentration ameliorate memory. Aβ aggregation induces neurotox­
icity that is dependent on NFTs formation. Therefore, the expression of
Aβ plaques is not a distinguishing marker between natural aging and AD
brain [137,138]. However, few studies have supported the fact of
focusing tau and Aβ as potential target for drug therapy in AD [139,
140]. Moreover, Aβ act as a stimulus for inflammation that excites glial
cells to produce pro-inflammatory cytokines such as TNF-α, IL-6 and
IL-1β and inflammatory reaction protein like C-reactive protein (CRP).

Fig. 3. Schematic illustration of BA inhibiting/reducing the AChE activity in cholinergic pathway involved in AD pathogenesis. Ch- choline; ACh- acetylcholine; A-
acetate; a7nAchR- α7 nicotinic acetylcholine receptor; AChE- acetycholinesterase; TNF-α - tumor necrosis factor α; IL 6/1β- interleukin 6/1β; NF-kB- nuclear factor
kappa-light-chain-enhancer of activated B cells; Aβ- amyloid-beta; BA- boswellic acid.

6
A. Siddiqui et al.
These agents have the potential to further stimulate glial cells to release
phosphorylated tau, Aβ42 and other pro-inflammatory mediators [141].
On the other hand, enhanced IL-1β and other cytokines expression also
trigger CDK5 to activate tau hyperphosphorylation which leads to the
formation of NFTs [27].
At present, most of the research studies have been focused on Aβ and
Tau pathology to achieve the goal of AD therapy [142–144]. A study
shows the effect of β-BA on the outgrowth of neurite and branching of
hippocampus neurons by Karima et al. [145]. They reported that β-BA
has the potential to improve branching, the outgrowth of neurite, and
advances tubulin polymerization. Afterward, they studied the mecha­
nism of β-BA on the tubulin assembly and the results shows that βBA has
significantly strengthened microtubule polymerization and increases the
length of microtubules, which protected microtubule disorientation and
axonal degradation as well. Therefore, it can be concluded that βBA
could be a valuable agent against neurodegenerative diseases [146].
Another study in rodents demonstrated that AKBA downregulated the
expression of BACE1, which is responsible for the cleavage of APP,
therefore, inhibiting Aβ accumulation in AD brains. Simultaneously,
AKBA also exerts anti-inflammatory and antioxidant effects by inhibit­
ing the release of inflammatory mediators [82].
Many studies have been conducted so far, including the effect of
terpenoids on Aβ plaques and neurofibrillary tangle formation [147,
148]. Similarly, another research study of α-BA on primary fetal human
cell lines against streptozotocin-induced AD hallmarks in astrocytes such
as hyperphosphorylated tau, cell death and ROS formation shows a
significant potential decrease in tau hyperphosphorylation, ROS for­
mation and improved cell proliferation [149]. A recent study demon­
strated anti-inflammatory effect of BAs in lipopolysaccharide (LPS)
stimulated microglial cells via down regulating expression of inflam­
matory molecules such as IL-1β, IL-6, inducible nitric oxide synthase
(iNOS) and NF-kB [150]. In the Aβ-induced rodent model of depression,
Fig. 4. Represents the potential role of BA inhibiting Aβ plaques and NFT induced inflammatory and neurotoxicity mechanism in AD. NF-kB- nuclear factor kappa-
light-chain-enhancer of activated B cells; iNOS- inducible nitric oxide synthase; TNF-α - tumor necrosis factor a; IL-1β/6 - Interleukin 1β/6; ROS- reactive oxygen
species; BACE1- beta-site APP cleaving enzyme 1; APP- amyloid precursor protein; Aβ- amyloid-beta; CDK5- cyclin dependant kinase enzyme; P- phosphorylation;
BA- boswellic acid; AD- Alzheimer’s disease.
7
Biomedicine & Pharmacotherapy 144 (2021) 112250
it was demonstrated that sublingually administered AKBA (5 mg/kg)
have reverted depressive like symptoms due to its anti-glutaminergic
and antioxidant properties. In addition, such treatment also caused a
reduction in glial fibrillary acid protein (GFAP), glutamate (GLU),
kynurenine (KYN) and NF-kB in hippocampus and prefrontal cortex
region [46]. These results suggest further molecular investigations are
required to explore the potential of BAs (Fig. 4) as a drug candidate
against tau and Aβ associated pathophysiology.
4. Future prospective
In the last few decades, different pathological hallmarks involved in
AD have been studied thoroughly. However, the target-oriented drug
approach is still left out. The present review has discussed the patho­
physiological changes in the brain resulting from AD involving disrup­
tion in Nrf2 and NF-kB crosstalk, ACh pathway, Aβ plaque accumulation
and, NFTs formation, ultimately leading to inflammation and cytotoxic
mechanisms activation. Numerous compounds have shown their po­
tency alone or in combination against AD, such as donepezil, galant­
amine, memantine, rivastigmine [151]. Natural compounds, on the
other hand, are winning more attention as they have a therapeutic index
with possibly no side effects and are affordable for long-run treatment in
chronic diseases [152]. The plant derivatives have broadened the scope
of the medicinal system. Likewise, a group of compounds known as
boswellic acids were considered as valuable as gold and used in religious
ceremonies in olden days. Now, BAs have reattained its reputation due
to its pleiotropic biological activities. However, AKBA is one of the most
potent bioactive constituent among BAs, which has shown assuring re­
sults as a potential candidate against inflammation induced AD pathway
in basic research studies. Further investigations on boswellia extract’s
phytoconstituents including AKBA activity on different signaling path­
ways are needed to be explored; also, there is a requirement to study its
A. Siddiqui et al.
bioavailability, drug interactions and pharmacokinetic properties.
5. Conclusion
Based on evidences it is concluded that inflammation plays a crucial
role in AD pathophysiology. Research studies help in establishing that
inflammation is a response to protein accumulation in the brain and
vice-versa. After all these investigations, there are still limited treatment
options available that have not been able to inhibit/modulate the
pathways involved in inflammation associated- neurodegeneration in
AD. On the other hand, boswellic acids are diverse in nature due to its
therapeutic efficacy in different types of diseases. In different AD
models, boswellic acids have demonstrated beneficial effects via
modulating the activity of multiple molecular targets and signaling
pathways that contribute to the pathogenesis of AD. Further in­
vestigations of BAs in inflammation-induced neurodegeneration should
be explored to ascertain its pharmacological aspects.
CRediT authorship contribution statement
AS and YK carried out literature review, conceptualized, designed
and drafted the manuscript. ZS, RNJ and IO have provided critical
suggestions and corrected the final version of manuscript. All authors
read and approved the final manuscript.
Conflict of interest statement
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
We thank Jeffrey Cheah School of Medicine and Health Sciences,
Monash University Malaysia for School Collaborative Grant 2021 (MED/
SCG2021/07; SED-000064), for the financial support to our work on the
neurodegeneration and possible alternative therapeutic targets, which
was the starting point of this review article.
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