Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins
Noradrenaline (NA) depletion occurs in Alzheimer’s disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin wer...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-7737/12/9/1264 |
| _version_ | 1797581166909325312 |
|---|---|
| author | Chiara Prinzi Anna Kostenko Gioacchino de Leo Rosario Gulino Giampiero Leanza Antonella Caccamo |
| author_facet | Chiara Prinzi Anna Kostenko Gioacchino de Leo Rosario Gulino Giampiero Leanza Antonella Caccamo |
| author_sort | Chiara Prinzi |
| collection | DOAJ |
| description | Noradrenaline (NA) depletion occurs in Alzheimer’s disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential. |
| first_indexed | 2024-03-10T23:01:26Z |
| format | Article |
| id | doaj.art-6b73d577d3e0465cb2b9994de6cdbdae |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-10T23:01:26Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-6b73d577d3e0465cb2b9994de6cdbdae2023-11-19T09:39:18ZengMDPI AGBiology2079-77372023-09-01129126410.3390/biology12091264Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological ProteinsChiara Prinzi0Anna Kostenko1Gioacchino de Leo2Rosario Gulino3Giampiero Leanza4Antonella Caccamo5Department of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyB.R.A.I.N. (Basic Research and Integrative Neuroscience) Laboratory for Neurogenesis and Repair, Department of Life Sciences, University of Trieste, 34100 Trieste, ItalySISSA, Scuola Internazionale Superiore di Studi Avanzati, 34136 Triste, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95125 Catania, ItalyDepartment of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyDepartment of Drug and Health Sciences, University of Catania, 95125 Catania, ItalyNoradrenaline (NA) depletion occurs in Alzheimer’s disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.https://www.mdpi.com/2079-7737/12/9/1264locus coeruleusAlzheimer’s diseaseTDP-43Taucognitive impairmentrat |
| spellingShingle | Chiara Prinzi Anna Kostenko Gioacchino de Leo Rosario Gulino Giampiero Leanza Antonella Caccamo Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins Biology locus coeruleus Alzheimer’s disease TDP-43 Tau cognitive impairment rat |
| title | Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins |
| title_full | Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins |
| title_fullStr | Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins |
| title_full_unstemmed | Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins |
| title_short | Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins |
| title_sort | selective noradrenaline depletion in the neocortex and hippocampus induces working memory deficits and regional occurrence of pathological proteins |
| topic | locus coeruleus Alzheimer’s disease TDP-43 Tau cognitive impairment rat |
| url | https://www.mdpi.com/2079-7737/12/9/1264 |
| work_keys_str_mv | AT chiaraprinzi selectivenoradrenalinedepletionintheneocortexandhippocampusinducesworkingmemorydeficitsandregionaloccurrenceofpathologicalproteins AT annakostenko selectivenoradrenalinedepletionintheneocortexandhippocampusinducesworkingmemorydeficitsandregionaloccurrenceofpathologicalproteins AT gioacchinodeleo selectivenoradrenalinedepletionintheneocortexandhippocampusinducesworkingmemorydeficitsandregionaloccurrenceofpathologicalproteins AT rosariogulino selectivenoradrenalinedepletionintheneocortexandhippocampusinducesworkingmemorydeficitsandregionaloccurrenceofpathologicalproteins AT giampieroleanza selectivenoradrenalinedepletionintheneocortexandhippocampusinducesworkingmemorydeficitsandregionaloccurrenceofpathologicalproteins AT antonellacaccamo selectivenoradrenalinedepletionintheneocortexandhippocampusinducesworkingmemorydeficitsandregionaloccurrenceofpathologicalproteins |