- ACE2 is SARS-CoV-2's primary receptor and RAS regulator, converting angiotensin II to angiotensin 1-7, modulating blood pressure and inflammatory pathways.
- Plasma membrane lipid composition, notably cholesterol-rich lipid rafts, controls ACE2 localisation and viral accessibility; dyslipidaemia increases susceptibility to severe COVID-19.
- Aberrant lipid metabolism in COVID-19 and Long COVID parallels mechanisms in Alzheimer's and Parkinson's, linking systemic inflammation to accelerated neurodegeneration and therapeutic opportunities.
Mol Aspects Med. 2026 Sep 17;112:101519. doi: 10.1016/j.mam.2026.101519. Online ahead of print.
ABSTRACT
Angiotensin-converting enzyme 2 (ACE2) is the primary cellular receptor of SARS-CoV-2. It is a key regulator of the renin-angiotensin system (RAS) and modulates blood pressure and inflammatory pathways. ACE2 converts pro-inflammatory angiotensin II into the vasoprotective peptide, angiotensin (1-7). This is strongly influenced by the lipid composition of the plasma membrane. Cholesterol-rich lipid rafts play an important role in determining receptor localisation and viral accessibility. Dyslipidaemia, which is common in obesity, diabetes, and metabolic syndrome, has been associated with an increased susceptibility to severe COVID-19 and may amplify systemic inflammation. Aberrant lipid metabolism also contributes to neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, which drive neuroinflammation, synaptic dysfunction, and blood-brain barrier impairment. Notably, similar disturbances and systemic inflammation are increasingly recognised in patients with Long COVID, suggesting overlapping mechanisms that may exacerbate or accelerate neurodegenerative processes. This review explores the interplay between ACE2 regulation, lipid metabolism, and systemic inflammation in COVID-19, with a particular focus on their implications for neurological health. Uniquely, we highlighted the intersection of ACE2 and lipid-related alterations in patients with Long COVID and their potential contribution to the progression of neurodegenerative diseases. In addition, we reviewed therapeutic strategies targeting ACE2, including recombinant soluble ACE2, ACE2-based nanotherapeutics, and lipid-focused interventions, aimed at mitigating acute infection, systemic inflammation, and persistent neurological sequelae. Understanding these mechanisms is essential to prevent long-term neurological consequences of the COVID-19 pandemic.
PMID:42753425 | DOI:10.1016/j.mam.2026.101519
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