Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (t1/2α ranging from 1.25 to 3 min) followed by a slower elimination phase (t1/2β ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g−1 s−1, consistent with penetration across the blood–brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.

Background The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a major cause of death, particularly in the elderly. The geriatric population in which cognitive decline due to Alzheimer’s disease (AD) is frequent is disproportionately affected by the pandemic. In addition, central nervous system (CNS) manifestations have been reported in a significant subset of SARS‐CoV‐2 infected patients. Method Since the principal entry receptor utilized by SARS‐COV‐2 is Angiotensin‐Converting Enzyme 2 (ACE2), we examined whether ACE2 protein and mRNA levels were altered postmortem in parietal cortex samples from two different AD cohorts, totalling 142 cases. Results Both immunoblot and RT‐qPCR analysis revealed higher concentrations of ACE2 protein and mRNA in persons with a neuropathological diagnosis of AD, compared to age‐matched controls. Brain levels of ACE2 were inversely correlated with antemortem cognitive scores. We found that ACE2 protein was highly enriched in microvessels of mice compared to brain parenchyma, but not in humans. Detachment of ACE2 from brain cell membranes was strongly associated with pericytes loss. No significant change of ACE2 protein was detected in the parietal cortex from the 3xTg‐AD mouse model of AD neuropathology. Conclusion Our data suggest that cognitive impairment is associated with higher levels of ACE2 in the brain, which might contribute the higher risk of CNS SARS‐CoV‐2 infection in cognitively impaired individuals and AD patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFRβ, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-β peptides (Aβ) concentrations (p = 0.01) and insoluble phospho-tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.