ACE2 correlation to TGF-β
Recent studies have reported an inverse relationship between ACE2 and
transforming growth factor-β (TGF-β). In cancer models, decreased levels
of ACE2 correlated with increased levels of TGF-β. 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-β and
other inflammatory pathways. Moreover, patients with severe COVID-19
symptoms had higher blood serum TGF-β concentrations than those with
mild symptoms, thus further implicating the role of TGF-β and warranting
further investigation. Interestingly, reduced angiotensin/ACE2 activity
has been associated with tau hyperphosphorylation and increased amyloid
beta (Aβ) 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].