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 Aß 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.
| Original language | English |
|---|---|
| Article number | 61 |
| Journal | Acta neuropathologica communications |
| Volume | 6 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Feb 23 2018 |
Fingerprint
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience
Cite this
Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer's disease. / Borin, Mirta; Saraceno, Claudia; Catania, Marcella; Lorenzetto, Erika; Pontelli, Valeria; Paterlini, Anna; Fostinelli, Silvia; Avesani, Anna; Fede, Giuseppe Di; Zanusso, Gianluigi; Benussi, Luisa; Binetti, Giuliano; Zorzan, Simone; Ghidoni, Roberta; Buffelli, Mario; Bolognin, Silvia.
In: Acta neuropathologica communications, Vol. 6, No. 1, 61, 23.02.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rac1 activation links tau hyperphosphorylation and Aß dysmetabolism in Alzheimer's disease
AU - Borin, Mirta
AU - Saraceno, Claudia
AU - Catania, Marcella
AU - Lorenzetto, Erika
AU - Pontelli, Valeria
AU - Paterlini, Anna
AU - Fostinelli, Silvia
AU - Avesani, Anna
AU - Fede, Giuseppe Di
AU - Zanusso, Gianluigi
AU - Benussi, Luisa
AU - Binetti, Giuliano
AU - Zorzan, Simone
AU - Ghidoni, Roberta
AU - Buffelli, Mario
AU - Bolognin, Silvia
PY - 2018/2/23
Y1 - 2018/2/23
N2 - 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 Aß 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.
AB - 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 Aß 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.
UR - http://www.scopus.com/inward/record.url?scp=85053419747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053419747&partnerID=8YFLogxK
U2 - 10.1186/s40478-018-0567-4
DO - 10.1186/s40478-018-0567-4
M3 - Article
AN - SCOPUS:85053419747
VL - 6
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
SN - 2051-5960
IS - 1
M1 - 61
ER -