Alzheimer’s Disease (AD) is the most common form of dementia. Regarding physiopathology, the key event is currently considered the aggregation and deposition of the beta-amyloid peptide (Aβ). However, neuroinflammation is postulated to play an essential role. Besides altered cognition, one of the main causes of distress in caregivers of AD patients is represented by Behavioural and Psychological Symptoms of Dementia (BPSD). Among them, aggression and agitation (A/A) represent a serious clinical problem, requiring qualified people and specialized structures. BPSD biological bases are still unknown and no definitive pharmacological treatments are available. Translocator protein 18-kDa (TSPO-18) is a receptor located on the outer mitochondrial membrane, formerly known as the Peripheral Benzodiazepine Receptor due to its pharmacological properties. TSPO is up-regulated in microglia in AD and is considered a biomarker of neuroinflammation, employed as a target for PET tracers (e.g., PK11195). The endogenous ligand is DBI (Diazepam Binding Inhibitor) that acts as an inverse agonist on GABAA receptors as well (i.e., as an anxiogenic peptide). TSPO transports cholesterol from cytoplasm to mitochondria in order to start the biosynthesis of neurosteroids. A reduction in TSPO expression in PBMCs and changes in serum neurosteroids levels have been shown in patients with anxiety disorder. Moreover, exon 4 of the TSPO gene contains a SNP called rs6971 (Ala147Thr substitution) that has been associated to separation anxiety. Finally, TSPO is also expressed on the plasma membrane of peripheral blood monocytes, where regulates chemotaxis and the passage through the blood-brain barrier (BBB) for contributing to the inflammatory milieu. Given TSPO involvement in neuroinflammation, steroids’ biosynthesis and anxiety genesis, this receptor seems an interesting target of study for understanding BPSD. At the moment, we genotyped 40 AD patients for rs6971 and we measured TSPO mRNA levels in their PBMC. Moreover, we assessed neurotrophins and DBI serum concentrations in the same patients. All the patients were screened for BPSD with the NPI and disease severity was evaluated by the MMSE. Moreover, we performed chemotaxis assays using THP-1 cells (acute myeloid leukaemia cell line) and MCP-1/Aβ peptide as chemoattractants, in order to get preliminary results about cellular migration in the presence of Aβ. We plan to run the same experiments on monocytes obtained from our patients. Further step will be including a model of BBB (transmigration assay). Our final goal is to find out whether these biological aspects could be linked to the presence of more or less severe BPSD, in order to cast light on the real determinants of these serious dementia-associated symptoms

Grana, D., Conti, E., Zoia, C., Maggioni, L., Arosio, A., Stefanoni, G., et al. (2016). Behavioural anomalies in neurodegenerative diseases: role of the immune response. In Abstract book (pp.S33-S33).

Behavioural anomalies in neurodegenerative diseases: role of the immune response

Grana, D
Primo
;
Conti, E
Secondo
;
Zoia, C;MAGGIONI, LAURA;AROSIO, ANDREA MARIO LUCIANO;Stefanoni, G;ALIPRANDI, ANGELO;Appollonio, I;Ferrarese, C
Penultimo
;
Tremolizzo, L
Ultimo
2016

Abstract

Alzheimer’s Disease (AD) is the most common form of dementia. Regarding physiopathology, the key event is currently considered the aggregation and deposition of the beta-amyloid peptide (Aβ). However, neuroinflammation is postulated to play an essential role. Besides altered cognition, one of the main causes of distress in caregivers of AD patients is represented by Behavioural and Psychological Symptoms of Dementia (BPSD). Among them, aggression and agitation (A/A) represent a serious clinical problem, requiring qualified people and specialized structures. BPSD biological bases are still unknown and no definitive pharmacological treatments are available. Translocator protein 18-kDa (TSPO-18) is a receptor located on the outer mitochondrial membrane, formerly known as the Peripheral Benzodiazepine Receptor due to its pharmacological properties. TSPO is up-regulated in microglia in AD and is considered a biomarker of neuroinflammation, employed as a target for PET tracers (e.g., PK11195). The endogenous ligand is DBI (Diazepam Binding Inhibitor) that acts as an inverse agonist on GABAA receptors as well (i.e., as an anxiogenic peptide). TSPO transports cholesterol from cytoplasm to mitochondria in order to start the biosynthesis of neurosteroids. A reduction in TSPO expression in PBMCs and changes in serum neurosteroids levels have been shown in patients with anxiety disorder. Moreover, exon 4 of the TSPO gene contains a SNP called rs6971 (Ala147Thr substitution) that has been associated to separation anxiety. Finally, TSPO is also expressed on the plasma membrane of peripheral blood monocytes, where regulates chemotaxis and the passage through the blood-brain barrier (BBB) for contributing to the inflammatory milieu. Given TSPO involvement in neuroinflammation, steroids’ biosynthesis and anxiety genesis, this receptor seems an interesting target of study for understanding BPSD. At the moment, we genotyped 40 AD patients for rs6971 and we measured TSPO mRNA levels in their PBMC. Moreover, we assessed neurotrophins and DBI serum concentrations in the same patients. All the patients were screened for BPSD with the NPI and disease severity was evaluated by the MMSE. Moreover, we performed chemotaxis assays using THP-1 cells (acute myeloid leukaemia cell line) and MCP-1/Aβ peptide as chemoattractants, in order to get preliminary results about cellular migration in the presence of Aβ. We plan to run the same experiments on monocytes obtained from our patients. Further step will be including a model of BBB (transmigration assay). Our final goal is to find out whether these biological aspects could be linked to the presence of more or less severe BPSD, in order to cast light on the real determinants of these serious dementia-associated symptoms
abstract + poster
Alzheimer’s Disease (AD), Behavioural and Psychological Symptoms of Dementia (BPSD), Translocator protein 18-kDa (TSPO-18), neuroinflammation, chemotaxis, neurosteroids, rs6971, THP-1
English
European Meeting of Neuroscence by PhD students
2016
Abstract book
2016
53
suppl 1
S33
S33
none
Grana, D., Conti, E., Zoia, C., Maggioni, L., Arosio, A., Stefanoni, G., et al. (2016). Behavioural anomalies in neurodegenerative diseases: role of the immune response. In Abstract book (pp.S33-S33).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/127459
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