Cerebrospinal fluid and frontal cortex TMPRSS2 and ACE2 protein levels differ in Down syndrome and Alzheimer's disease.

Individuals with Down syndrome (DS) and Alzheimer’s disease (AD) are vulnerable to COVID-19, but whether alterations in ACE2, the viral receptor, and TMPRSS2, the spike-priming protease for SARS-CoV-2, differ between these disorders is unknown. We analyzed cleaved fragments and full-length species of ACE2 and TMPRSS2 in the cerebrospinal fluid (CSF) from non-infected individuals with DS (n = 9) without memory decline (nDS), DS with dementia (dDS; n = 10) and aged matched controls (n = 10). CSF levels were compared to levels in frozen postmortem frontal cortex in nDS (n = 4), dDS (n = 8) and 11 controls using quantitative fluorescent western blotting. We also examined CSF (19 AD and 19 age-matched non-AD controls) and frontal cortex from 30 AD cases and 7 non-disease controls. CSF and frontal cortex TMPRSS2 full-length zymogen and active protease-domain fragment were significantly increased in nDS, but not in dDS despite elevated zymogen. In contrast, AD CSF and frontal cortex levels of the TMPRSS2 protease fragment and zymogen remained unchanged. Regarding the viral receptor, an ~ 80 kDa fragment of ACE2 was significantly reduced in nDS CSF compared to controls, whereas there was a significant decrease in an ACE2 fragment/full-length quotient in both nDS and dDS. In frontal cortex, full-length ACE2 levels were preserved in nDS compared to controls, but several ACE2 species (120 and 110 kDa full-length, and 80 kDa fragment) were significantly decreased in dDS compared to nDS and controls. In contrast, CSF ACE2 130 kDa full-length levels were decreased compared to an increase in the fragment/full-length ratio in AD compared to controls, opposite to DS. In AD, frontal cortex levels of the 150 kDa ACE2 full-length species was significantly reduced across all Braak stages. ACE2 immunohistochemistry and immunofluorescence of frontal cortex sections revealed positive puncta in the neuropil, astrocytes and blood vessels in AD and DS with or without dementia. Overall, we found an increase in active TMPRSS2 and reduced soluble ACE2 fragments individuals with DS, particularly those without dementia, which differs from that observed in AD that may differentially affect susceptibility to COVID-19 viral infection in these conditions.