Abstract Body: SARS-COV-2 causes neurological and cognitive impairments and aggravates Alzheimer’s Disease-Related Dementia (ADRD). Yet, the molecular mechanism is not fully understood. We have previously shown that SARS-CoV-2 spike protein disturbs the brain's renin-angiotensin system (RAS) and increases cerebrovascular inflammation. We hypothesize that SARS-CoV-2 spike protein will accelerate hypoxia-induced ADRD via augmenting cerebrovascular inflammation and impairing blood-brain-barrier (BBB) functions. We propose that the pharmacological restoration of the RAS balance using Losartan, an AT₁ receptor blocker, will improve SARS-CoV-2 spike protein-induced ADRD.
Methods: Hypoxia-induced ADRD was produced in humanized ACE2 mice, a COVID-19 mouse model, using a permanent unilateral common carotid artery ligation (UCCL). Cerebral hypoxia was confirmed by laser speckle imaging. hACE-2 mice received either vehicle, SARS-CoV-2 spike protein via jugular vein, or spike protein with Losartan (10 mg/kg) in drinking water after UCCL. ADRD was assessed via Novel Object Recognition at baseline, seven days, and fourteen days after surgery. Cerebrovascular inflammatory markers and tight junction proteins (TNF-α, Il-6, VEGF, MMP-9, and occludin) were measured in brain homogenate using RT-PCR and Western Blots.
Results: Blood flow analysis confirmed cerebrovascular hypoxia in all groups. Spike protein further decreased cerebral blood flow, which was prevented with Losartan (P<0.05). Spike protein significantly increased inflammatory markers and worsened BBB functions after UCCL, which were mitigated by Losartan (P<0.05). Spike protein aggravated cognitive impairment after UCCL, which was attenuated by Losartan (P<0.05).
In conclusion, the SARS-CoV-2 spike protein accelerates Alzheimer’s Disease-Related Dementia through increased cerebrovascular inflammation and deterioration of BBB in hACE2 Mice. The AT₁R blocker Losartan attenuated the detrimental effect of the spike protein by reducing cerebrovascular inflammation and improving cerebral blood flow.