ABSTRACT
Rapidly emerging evidence has characterized the association between vascular dementia (VaD) and increased
COVID-19 incidence, morbidity, and post-COVID cognitive decline. We theorize that brain vascular pathology in
VaD and additional pathophysiologic features such as blood-brain barrier (BBB) disruption and reduced cerebral
blood flow may directly contribute to both VaD and COVID-19. Several lines of evidence support this hypothesis.
First, we have demonstrated that SARS-CoV-2 binds to the vascular integrin a5ß1 receptor to infect cells, the
same receptor we have also linked to BBB disruption in brain ischemia (stroke) models and chronic bilateral
carotid artery stenosis (BCAS), which models pathophysiological aspects of VaD such as reduced cerebral blood
flow, BBB disruption, neuroinflammation, white matter damage, and cognitive decline. Second, integrin a5ß1 is
substantially upregulated in an age-dependent fashion (aged>young) in the brain vasculature after stroke and
BCAS, and inhibition of this receptor with the clinically-validated integrin a5ß1 pentapeptide inhibitor ATN-161
lessens BBB disruption and cognitive impairment in these models. Third, SARS-CoV-2 infection also increases
integrin a5ß1 expression in vivo and disrupts the BBB. Forth, preliminary results suggest that SARS-CoV-2
infection after BCAS further increases morbidity vs. BCAS or infection alone and accelerates brain vascular
integrin a5ß1 upregulation. Fifth, ATN-161 inhibits SARS-CoV-2 infection in vitro and in vivo and prevents SARS-
CoV-2-induced increased expression of a5ß1 integrin. Finally, although angiotensin-converting enzyme 2
(ACE2) is the canonical receptor for viral entry (internalization and fusion) into host cells, its ectodomain binds
the viral spike protein (S-protein) on the surface to facilitate virus attachment and access into host cells through
receptor-mediated endocytosis using an RGD motif. As many cell-surface integrins also bind RGD, we and
others have provided compelling evidence that integrins are co-receptors of the virus. Additionally, we have
shown that talin-dependent integrin activation is required for SARS-CoV-2 infectivity. Consistent with our results,
previous studies have shown that a5ß1 and ACE2 engage in signaling crosstalk likely driven by mutual
interaction at their cytoplasmic tails. Building on these findings, we hypothesize that (i) integrin a5ß1 plays an
important age-dependent pathogenic role in the association between SARS-CoV-2 infection and VaD by
worsening pre-existing VaD after COVID-19, (ii) ATN-161 treatment before, during, or after COVID-19 infection
will stabilize BBB integrity to improve COVID-19 neurocognitive outcomes in the context of pre-existing vascular
dementia, and (iii) integrin a5ß1 signaling regulates infectivity, and its upregulation potentiates dysregulation of
the BBB. To investigate these hypotheses, we propose to 1). Demonstrate that experimental VaD worsens
COVID-19 morbidity and subsequent cognitive decline, 2). Determine the therapeutic potential of integrin a5ß1
inhibition in improving VaD post-COVID morbidity and cognitive decline, 3). Determine the signaling mechanism
of integrin a5ß1 required for SARS-CoV-2 productive infection and dysregulation of cell barrier function.
