Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease
Abstract One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been kno...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-07-01
|
| Series: | Acta Neuropathologica Communications |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0567-4 |
| _version_ | 1811197392066707456 |
|---|---|
| author | Mirta Borin Claudia Saraceno Marcella Catania Erika Lorenzetto Valeria Pontelli Anna Paterlini Silvia Fostinelli Anna Avesani Giuseppe Di Fede Gianluigi Zanusso Luisa Benussi Giuliano Binetti Simone Zorzan Roberta Ghidoni Mario Buffelli Silvia Bolognin |
| author_facet | Mirta Borin Claudia Saraceno Marcella Catania Erika Lorenzetto Valeria Pontelli Anna Paterlini Silvia Fostinelli Anna Avesani Giuseppe Di Fede Gianluigi Zanusso Luisa Benussi Giuliano Binetti Simone Zorzan Roberta Ghidoni Mario Buffelli Silvia Bolognin |
| author_sort | Mirta Borin |
| collection | DOAJ |
| description | Abstract One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics. |
| first_indexed | 2024-04-12T01:13:57Z |
| format | Article |
| id | doaj.art-11d0fb5036e34d868ddf83de50c56590 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-12T01:13:57Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-11d0fb5036e34d868ddf83de50c565902022-12-22T03:54:01ZengBMCActa Neuropathologica Communications2051-59602018-07-016111710.1186/s40478-018-0567-4Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s diseaseMirta Borin0Claudia Saraceno1Marcella Catania2Erika Lorenzetto3Valeria Pontelli4Anna Paterlini5Silvia Fostinelli6Anna Avesani7Giuseppe Di Fede8Gianluigi Zanusso9Luisa Benussi10Giuliano Binetti11Simone Zorzan12Roberta Ghidoni13Mario Buffelli14Silvia Bolognin15Department of Neurosciences, Biomedicine and Movement Sciences, University of VeronaMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliDivision of Neurology 5 and Neuropathology, IRCCS Foundation - Carlo Besta Neurological InstituteDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaDivision of Neurology 5 and Neuropathology, IRCCS Foundation - Carlo Besta Neurological InstituteDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliMAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliEnvironmental Research and Innovation (ERIN) Department, Luxembourg Institute of Science and Technology (LIST)Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliDepartment of Neurosciences, Biomedicine and Movement Sciences, University of VeronaMolecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio FatebenefratelliAbstract One of the earliest pathological features characterizing Alzheimer’s disease (AD) is the loss of dendritic spines. Among the many factors potentially mediating this loss of neuronal connectivity, the contribution of Rho-GTPases is of particular interest. This family of proteins has been known for years as a key regulator of actin cytoskeleton remodeling. More recent insights have indicated how its complex signaling might be triggered also in pathological conditions. Here, we showed that the Rho-GTPase family member Rac1 levels decreased in the frontal cortex of AD patients compared to non-demented controls. Also, Rac1 increased in plasma samples of AD patients with Mini-Mental State Examination < 18 compared to age-matched non demented controls. The use of different constitutively active peptides allowed us to investigate in vitro Rac1 specific signaling. Its activation increased the processing of amyloid precursor protein and induced the translocation of SET from the nucleus to the cytoplasm, resulting in tau hyperphosphorylation at residue pT181. Notably, Rac1 was abnormally activated in the hippocampus of 6-week-old 3xTg-AD mice. However, the total protein levels decreased at 7-months. A rescue strategy based on the intranasal administration of Rac1 active peptide at 6.5 months prevented dendritic spine loss. This data suggests the intriguing possibility of a dual role of Rac1 according to the different stages of the pathology. In an initial stage, Rac1 deregulation might represent a triggering co-factor due to the direct effect on Aβ and tau. However, at a later stage of the pathology, it might represent a potential therapeutic target due to the beneficial effect on spine dynamics.http://link.springer.com/article/10.1186/s40478-018-0567-4 |
| spellingShingle | Mirta Borin Claudia Saraceno Marcella Catania Erika Lorenzetto Valeria Pontelli Anna Paterlini Silvia Fostinelli Anna Avesani Giuseppe Di Fede Gianluigi Zanusso Luisa Benussi Giuliano Binetti Simone Zorzan Roberta Ghidoni Mario Buffelli Silvia Bolognin Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease Acta Neuropathologica Communications |
| title | Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease |
| title_full | Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease |
| title_fullStr | Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease |
| title_full_unstemmed | Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease |
| title_short | Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease |
| title_sort | rac1 activation links tau hyperphosphorylation and aβ dysmetabolism in alzheimer s disease |
| url | http://link.springer.com/article/10.1186/s40478-018-0567-4 |
| work_keys_str_mv | AT mirtaborin rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT claudiasaraceno rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT marcellacatania rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT erikalorenzetto rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT valeriapontelli rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT annapaterlini rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT silviafostinelli rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT annaavesani rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT giuseppedifede rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT gianluigizanusso rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT luisabenussi rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT giulianobinetti rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT simonezorzan rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT robertaghidoni rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT mariobuffelli rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease AT silviabolognin rac1activationlinkstauhyperphosphorylationandabdysmetabolisminalzheimersdisease |