In the world of Alzheimer’s disease, it’s like we have an ACE up our sleeve. Amyloid β-protein 1-42 (Aβ42) is a troublemaker that accumulates in the brain and contributes to the disease. But fear not! Angiotensin-converting enzyme (ACE) steps in to save the day by converting Aβ42 into its less harmful counterpart, Aβ40. However, when Presenilin 1 (PS1), a protein associated with familial cases of Alzheimer’s, goes missing or becomes faulty, it throws off this delicate balance. Our scientific heroes discovered that PS1 deficiency alters the activity of ACE, impairing its ability to convert Aβ42 to Aβ40 and reducing its angiotensin-converting activity. This means that PS1 deficiency and PSEN1 mutations may contribute to the higher levels of Aβ42 observed in Alzheimer’s patients. These findings shed light on a possible mechanism behind the disease and highlight the importance of ACE in maintaining brain health. So grab your lab coats and dive deeper into the fascinating research by following the link below!
IntroductionAlzheimer’s disease (AD) is associated with amyloid β-protein 1-42 (Aβ42) accumulation in the brain. Aβ42 and Aβ40 are the major two species generated from amyloid precursor protein. We found that angiotensin-converting enzyme (ACE) converts neurotoxic Aβ42 to neuroprotective Aβ40 in an ACE domain– and glycosylation-dependent manner. Presenilin 1 (PS1) mutations account for most of cases of familial AD and lead to an increased Aβ42/40 ratio. However, the mechanism by which PSEN1 mutations induce a higher Aβ42/40 ratio is unclear.MethodsWe over expressed human ACE in mouse wild-type and PS1-deficient fibroblasts. The purified ACE protein was used to analysis the Aβ42-to-Aβ40- and angiotensin-converting activities. The distribution of ACE was determined by Immunofluorescence staining.ResultWe found that ACE purified from PS1-deficient fibroblasts exhibited altered glycosylation and significantly reduced Aβ42-to-Aβ40- and angiotensin-converting activities compared with ACE from wild-type fibroblasts. Overexpression of wild-type PS1 in PS1-deficient fibroblasts restored the Aβ42-to-Aβ40- and angiotensin-converting activities of ACE. Interestingly, PS1 mutants completely restored the angiotensin-converting activity in PS1-deficient fibroblasts, but some PS1 mutants did not restore the Aβ42-to-Aβ40-converting activity. We also found that the glycosylation of ACE in adult mouse brain differed from that of embryonic brain and that the Aβ42-to-Aβ40-converting activity in adult mouse brain was lower than that in embryonic brain.ConclusionPS1 deficiency altered ACE glycosylation and impaired its Aβ42-to-Aβ40- and angiotensin-converting activities. Our findings suggest that PS1 deficiency and PSEN1 mutations increase the Aβ42/40 ratio by reducing the Aβ42-to-Aβ40-converting activity of ACE.
Dr. David Lowemann, M.Sc, Ph.D., is a co-founder of the Institute for the Future of Human Potential, where he leads the charge in pioneering Self-Enhancement Science for the Success of Society. With a keen interest in exploring the untapped potential of the human mind, Dr. Lowemann has dedicated his career to pushing the boundaries of human capabilities and understanding.
Armed with a Master of Science degree and a Ph.D. in his field, Dr. Lowemann has consistently been at the forefront of research and innovation, delving into ways to optimize human performance, cognition, and overall well-being. His work at the Institute revolves around a profound commitment to harnessing cutting-edge science and technology to help individuals lead more fulfilling and intelligent lives.
Dr. Lowemann’s influence extends to the educational platform BetterSmarter.me, where he shares his insights, findings, and personal development strategies with a broader audience. His ongoing mission is shaping the way we perceive and leverage the vast capacities of the human mind, offering invaluable contributions to society’s overall success and collective well-being.