Carriers of heterozygous loss-of-function ACE mutations are at risk for Alzheimer’s disease
Abstract Amyloid Aβ42 (constituents of the protein aggregates in the brains of patients with Alzheimer’s disease (AD) cleaved by ACE, and thus, a decrease in tissue ACE activity (constitutive or ACE inhibitor-induced) could be risk factor for AD. We hypothesized that subjects with heterozygous Loss-of-Function (LoF) ACE mutations are at risk for Alzheimer’s disease. Existing SNP databases were analyzed for LoF ACE mutations using PolyPhen-2 scores and compared with the topology of known ACE mutations already associated with AD. The combined frequency of >400 of these LoF-damaging ACE mutations in the general population is quite significant – up to 5 % – comparable with the frequency of AD in the population >70 years old. Our analysis suggests several mechanisms by which ACE mutations may be associated with Alzheimer’s disease. Systematic analysis of blood ACE levels in patients with all ACE mutations is likely to have clinical significance because available sequencing data will help detect persons with increased risk of late-onset Alzheimer’s disease. Patients with transport-deficient ACE mutations (about 20 % of damaging ACE mutations) may benefit from preventive or therapeutic treatment with a combination of chemical and pharmacological (e.g., centrally acting ACE inhibitors) chaperones and proteosome inhibitors to restore impaired surface ACE expression..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
ResearchSquare.com - (2023) vom: 03. Dez. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Danilov, Sergei M. [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.21203/rs.3.rs-2570701/v1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XRA038870304 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XRA038870304 | ||
| 003 | DE-627 | ||
| 005 | 20231204130942.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230307s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.21203/rs.3.rs-2570701/v1 |2 doi | |
| 035 | |a (DE-627)XRA038870304 | ||
| 035 | |a (ResearchSquare)10.21203/rs.3.rs-2570701/v1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Danilov, Sergei M. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Carriers of heterozygous loss-of-function ACE mutations are at risk for Alzheimer’s disease |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Amyloid Aβ42 (constituents of the protein aggregates in the brains of patients with Alzheimer’s disease (AD) cleaved by ACE, and thus, a decrease in tissue ACE activity (constitutive or ACE inhibitor-induced) could be risk factor for AD. We hypothesized that subjects with heterozygous Loss-of-Function (LoF) ACE mutations are at risk for Alzheimer’s disease. Existing SNP databases were analyzed for LoF ACE mutations using PolyPhen-2 scores and compared with the topology of known ACE mutations already associated with AD. The combined frequency of >400 of these LoF-damaging ACE mutations in the general population is quite significant – up to 5 % – comparable with the frequency of AD in the population >70 years old. Our analysis suggests several mechanisms by which ACE mutations may be associated with Alzheimer’s disease. Systematic analysis of blood ACE levels in patients with all ACE mutations is likely to have clinical significance because available sequencing data will help detect persons with increased risk of late-onset Alzheimer’s disease. Patients with transport-deficient ACE mutations (about 20 % of damaging ACE mutations) may benefit from preventive or therapeutic treatment with a combination of chemical and pharmacological (e.g., centrally acting ACE inhibitors) chaperones and proteosome inhibitors to restore impaired surface ACE expression. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Adzhubei, Ivan A. |4 aut | |
| 700 | 1 | |a Kozuch, Alex J. |4 aut | |
| 700 | 1 | |a Petukhov, Pavel A. |4 aut | |
| 700 | 1 | |a Popova, Isolda A. |4 aut | |
| 700 | 1 | |a Choudhury, Ananyo |4 aut | |
| 700 | 1 | |a Sengupta, Dhriti |4 aut | |
| 700 | 1 | |a Dudek, Steven M. |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ResearchSquare.com |g (2023) vom: 03. Dez. |
| 773 | 1 | 8 | |g year:2023 |g day:03 |g month:12 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.21203/rs.3.rs-2570701/v1 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XRA | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 03 |c 12 | ||