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\begin{document}

\title{Relationship between COVID-19 and Alzheimer's disease}



\author[1]{Rim Harfouch}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\textbf{Rim M. Harfouch}

Department of Microbiology and Biochemistry, Faculty of Pharmacy,
Tishreen University, Latakia, Syria.

Corresponding author's Email: rimharfouch@tishreen.edu.sy

\textbf{Abstract} :

Coronavirus disease 2019 (COVID-19), which is caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), is a life-threatening
disease, especially in elderly individuals and those with comorbidities.
The predominant clinical manifestation of COVID-19 is respiratory
dysfunction, while neurological presentations are increasingly being
recognized. SARS-CoV-2 invades host cells primarily via attachment of
the~spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor
expressed on cell membranes. Patients with Alzheimer's disease (AD) are
more susceptible to SARS-CoV-2 infection and prone to severe clinical
outcomes. Recent studies have revealed some common risk factors for AD
and COVID-19. An understanding of the association between COVID-19 and
AD and the potential related mechanisms may lead to the development of
novel approaches to treating both diseases. It is important to
understand the mechanisms by which SARS-CoV-2 invades the central
nervous system (CNS) and the associations and potential shared factors
between COVID-19 and AD.

\textbf{Keywords:} COVID-19, Alzheimer's disease, correlation, mechanism
of action

\textbf{Introduction:}

From the beginning of the COVID-19 outbreak, simultaneously with
treatment measures, health and preventive measures such as strict
quarantine, social distancing, hand washing, disinfection of various
surfaces, and wearing a mask among others, as health protocols to reduce
and cut off the transmission chain were on the agenda of governments and
health organizations {[}1, 2{]}. SARS-CoV-2 infects target cells
primarily via interaction of the receptor-binding domain of the S
protein with the cellular angiotensin-converting enzyme 2 (ACE2)
receptor after activation of the S protein by transmembrane serine
protease 2 (TMPRSS2) {[}3{]}. The S protein is composed of two
functional subunits, S1 and S2; S1 is responsible for receptor binding,
whereas S2 (the C-terminal domain) is specifically responsible for
viral-cellular membrane fusion {[}4,5{]}. Although SARS-CoV-2 primarily
targets the respiratory tract, causing fever, dry cough, sore throat,
fatigue, and dyspnoea {[}6{]}, the virus also results in dysfunction of
multiple organ systems outside the lung, including the kidneys, liver,
brain, heart, gastrointestinal tract and other organ, as ACE2 and other
candidate receptors are also expressed in these tissues {[}7{]}.

In fact, the central nervous system (CNS) complications have been
observed in more than 30\% of individuals with COVID-19 presenting with
a higher infection severity. Emerging studies have revealed the
neuroinvasive potential of SARS-CoV-2, with neurological manifestations
ranging from lethargy, headache, loss of smell and taste, delirium,
insomnia, brain inflammation, stroke, brain haemorrhage to cognitive
impairment {[}8{]}.

Various studies using cultured cells, animal models, and brain tissues
from patients who died of COVID-19, have independently revealed the
capacity of SARS-CoV-2 to invade the CNS {[}9{]}. Supporting evidence
from a postmortem study indicated the presence of viral RNA and proteins
in the brains of more than half (21 of 40) of German patients who died
of COVID-19 {[}10{]}. In addition, the presence of SARS-CoV-2 in the
cerebrospinal fluid (CSF) of infected individuals also confirms CNS
infection. Notably, by employing well-characterized human brain
organoids, researchers have visualized widespread infectivity of
SARS-CoV-2 and extensive death of virus-infected and nearby neuronal
cells, and found that the viral infection can be abrogated by
pretreatment with an ACE2 antibody or administration of CSF obtained
from patients with COVID-19 {[}11{]}. Moreover, brain imaging studies
have revealed the presence of multiple haemorrhagic lesions and changes
in the brain structure of patients infected with SARS-CoV-2, even in
milder cases {[}12{]}. Together, this evidence implies that SARS-CoV-2
has the ability to enter the CNS and cause neurological conditions.

In a recent study, diffuse neural inflammatory markers were found in
\textgreater{}80\% of COVID-19 patient brains, processes which could
contribute to the observed neurological symptoms {[}13{]}. Furthermore,
another pair of frequent symptoms of infection by SARS-CoV-2 are
hyposmia and hypogeusia, the loss of the ability to smell and taste,
respectively. Interestingly, hyposmia has been reported in early-stage
Alzheimer's disease (AD), and AD type II astrocytosis has been observed
in neuropathology studies of COVID-19 patients {[}14{]}.

\selectlanguage{greek}\textbf{ACE2 correlation to TGF-β}

\selectlanguage{english}Recent studies have reported an inverse relationship between ACE2 and
transforming growth factor-\selectlanguage{greek}β \selectlanguage{english}(TGF-\selectlanguage{greek}β\selectlanguage{english}). In cancer models, decreased levels
of ACE2 correlated with increased levels of TGF-\selectlanguage{greek}β. \selectlanguage{english}In the context of
SARS-CoV-2 infection, downregulation of ACE2 has been observed, leading
to increased fibrosis formation, as well as upregulation of TGF-\selectlanguage{greek}β \selectlanguage{english}and
other inflammatory pathways. Moreover, patients with severe COVID-19
symptoms had higher blood serum TGF-\selectlanguage{greek}β \selectlanguage{english}concentrations than those with
mild symptoms, thus further implicating the role of TGF-\selectlanguage{greek}β \selectlanguage{english}and warranting
further investigation. Interestingly, reduced angiotensin/ACE2 activity
has been associated with tau hyperphosphorylation and increased amyloid
beta (A\selectlanguage{greek}β\selectlanguage{english}) pathology in animal models of AD {[}15, 16{]}.

Neuroinflammation is recognized as another characteristic
pathophysiology of AD. Microglia and astrocytes are major sources of
cytokines in individuals with AD. Dysfunction of the immune system may
promote the release of proinflammatory cytokines and result in synaptic
damage, neuronal death, and inhibition of neurogenesis, which are
related to the pathogenesis of AD {[}17{]}.

Although accumulating evidence indicates that SARS-CoV-2 can enter the
CNS, the presence of the virus in the brain may not critically correlate
with the neurological conditions, as postmortem studies have noted
occurrence of pronounced neuropathological changes even in patients with
COVID-19 in whom the virus was not detected in the CNS. Instead,
extensive research on CSF and postmortem brain tissues has indicated
that immune dysfunction and pronounced neuroinflammation within the CNS
are the main driver of CNS damage and neurological symptoms in infected
individuals. Neuroinflammation might result directly from coronavirus
infection or from excessive peripheral inflammation. Both SARS-CoV-2 and
proinflammatory mediators may promote BBB disruption, allowing the virus
to cross the BBB, enter the CNS, and activate microglia and astrocytes,
triggering a neuroinflammatory cascade that may contribute to the onset
and progression of neurodegeneration{[}18{]}.

\textbf{Pathogen-associated molecular pattern (PAMP)}

Several previous studies have suggested that the S protein of SARS-CoV-2
might function as a pathogen-associated molecular pattern (PAMP) to
drive neuroinflammatory responses through activation of TLRs, which are
widely expressed on macrophages and microglia and may function as
pattern recognition receptors (PRRs) to recognize molecular sequences
common to bacterial and viral pathogens. Microglia have been shown to
express a wide range of PRRs, including TLRs, NOD-like~receptors, RAGE
and scavenger receptors. SARS-CoV-2 activates these receptors, possibly
eliciting neuroinflammatory responses and contributing to disease
progression and severity {[}19{]}.

Astrocytes are also important components of the intrinsic immune
response in the CNS following viral infection. An increased plasma
concentration of glial fibrillary acidic protein (GFAP), a hallmark of
astrocyte activation, is commonly detected in patients with moderate and
severe COVID-19. As components of the BBB, astrocytes are highly
sensitive to peripheral inflammation. In addition to responding to
signals from microglia, astrocytes also rapidly respond to
proinflammatory cytokines secreted by endothelial cells. Astrocytes
express inflammatory molecules that contribute to neuroinflammation and
neurodegeneration upon exposure to activated proinflammatory microglia,
including proinflammatory cytokines such as IL-6, IL-1\selectlanguage{greek}β \selectlanguage{english}and TNF-\selectlanguage{greek}α;
\selectlanguage{english}PAMPs; and danger-associated molecular patterns. These data clearly
indicate that microglia and astrocytes participate in neuroinflammatory
responses to viral infection of the CNS {[}20{]}.

\textbf{Conclusions:}

The mechanism by which the virus gains access to the CNS and why
patients with AD are at higher risk of virus infection are not well
understood.. Although people infected with SARS-CoV-2 frequently display
neurological symptoms, multiple manifestations remain unrecognized.
First, neurological symptoms are often ignored because the first goal is
to combat respiratory symptoms. In addition, clarifying the mechanisms
by which SARS-CoV-2 invades and spreads throughout the CNS is important
for preventing and ameliorating neurological symptoms. Studies are
imperatively needed to clarify the potential mechanisms underlying the
elevated susceptibility and mortality rate of AD patients to COVID-19
and discover preventive strategies to minimize~the risk of viral
infection among patients with AD.

\textbf{References:}

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