- Email: [email protected]
INVESTIGATING THE POTENTIAL OF NOVEL CURCUMIN DERIVATIVES IN TARGETING AND MODULATING TOXIC TAU OLIGOMERIC STRAINS
P1486
P4-405
Poster Presentations: Wednesday, July 19, 2017
MONOAMINERGIC CORRELATES OF DISINHIBITED BEHAVIOURS IN THE NOVEL TAU58/4 TRANSGENIC MOUSE MODEL FOR TAUOPATHY
Femke Valkenburg1,2, Debby Van Dam1,2,3, Yannick Vermeiren1,2,3, Tony Aerts1,2, Peter Paul De Deyn1,2,3,4,5, 1University of Antwerp, Wilrijk, Belgium; 2Institute Born-Bunge, Wilrijk, Belgium; 3University of Groningen, Groningen, Netherlands; 4Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; 5 Biobank, Institute Born-Bunge, Wilrijk, Belgium. Contact e-mail: Femke. [email protected] Background: Tauopathies, such as frontotemporal dementia (FTD), are characterized by both memory and behavioural alterations. Especially patients with the behavioural variant of FTD exhibit disinhibited behaviours, for instance aggression and sexual disinhibition. These disturbances have been linked with altered neurotransmitter systems including, most prominently, alterations in dopaminergic and serotonergic systems. We aimed to investigate whether neurochemical correlates of disinhibited behaviours are observable in the novel transgenic Tau58/4 tauopathy mouse model, similar to observations in patients. Thereby, we hope to enable future in-depth investigation of the underlying pathologic mechanisms. Methods: Heterozygous (HET) Tau58/4 mice (C57BL6/J background with P301S mutation in exon 10) and age-matched control wild-type (WT) littermates, aged 3 (HET n¼6; WT n¼8) or 9 months (HET n¼4; WT n¼4), underwent behavioural testing related to aggression (aggression-induced resident-intruder test) and sexual disinhibition (ovariectomized, hormonally primed stimulus females). Subsequently, levels of serotonin (5-HT), dopamine and (nor)epinephrine ((N)E), as well as their respective metabolites (5-hydroxy-3-indoleacetic acid (5HIAA), 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol) were quantified in regionally dissected brain samples by means of an optimised ultra-high performance liquid chromatography system, coupled with electrochemical detection. Results: Preliminary results indicated that HET animals aged 3 and 9 months exhibited more offensive behaviours (i.e. sniffing, aggressive grooming; 3 months p<0.001; 9 months p¼0.021), but less defensive behaviours (upright posture; 3 months p<0.001; 9 months p¼0.021) than WT controls. So far, we did not find significant differences in neurotransmitter composition between HET and WT animals of the same age with respect to frontal cortex (FC) and (hypo)thalamus ((h)THAL), apart from an agedependent neurochemical increase in the FC (NA p¼0.007, 5-HIAA p¼0.027 and 5-HT p¼0.027) and (h)THAL (NA p¼0.027 and 5-HIAA p¼0.011) of the WT group. Conclusions: Tau58/4 mice exhibited more aggressive behaviours and less defensive behaviours at both early and advanced stages of tauopathy compared with controls, indicating an increase in disinhibitionlike behaviours. Preliminary investigations in FC and (h)THAL, however, were not significant, possibly due to relatively small sample sizes. Results of additional age groups and behavioural experiments, as well as neurochemical results of extra analysed brain regions will be presented during the AAIC 2017 conference. P4-406
INVESTIGATING THE POTENTIAL OF NOVEL CURCUMIN DERIVATIVES IN TARGETING AND MODULATING TOXIC TAU OLIGOMERIC STRAINS
Filippa Lo Cascio1,2, Urmi Sengupta1, Antonio Palumbo Piccionello2, Andrea Pace2, Claudia Campanella2, Celeste Caruso Bavisotto2,
Rakez Kayed1, 1University of Texas Medical Branch, Galveston, TX, USA; University of Palermo, Palermo, Italy. Contact e-mail: [email protected]
2
Background: Tauopathies are devastating age-related neurodegenerative disorders, characterized by the pathological aggregation and accumulation of the microtubule-associated protein tau and its subsequent deposition in different aggregated forms, including neurofibrillary tangles (NFTs). Recent research suggest that NFTs are the least toxic form of tau aggregates. However, the smaller, dynamic and soluble tau oligomers have been shown to be more toxic and efficient seeds for the propagation of pathology as compared to NFTs. Tau oligomers are a heterogeneous group of biophysically and conformationally distinct tau multimers that manifest in many different conformations, termed tau oligomeric strains. Due to the dynamic nature of these strains, studies focusing on the mechanisms underlying their formation and characteristics are challenging. Importantly, different tau oligomeric strains could explain how the aggregation of the same protein causes different diseases, progression rates and phenotypes even between individuals within the same disorder. Thus, depleting the disease-relevant structures by using small molecules could be a powerful therapeutic strategy that targets toxicity regardless of other factors involved in the formation of tau oligomeric strains. Methods: Herein we screened newly synthetized curcumin-like compounds to target and modulate tau oligomeric strains toxicity. Modulating their conformations through the use of novel curcumin derivatives could be useful for the prevention of tau oligomers formation and toxicity. We used in vitro techniques such as Western Blot and direct ELISA as well as biophysical assays to characterize tau oligomeric strains and their reactivity with tau oligomer specific polyclonal and monoclonal antibodies, T22 and TOMA respectively, in the presence and absence of curcumin derivatives. Results: Interestingly, novel curcumin derivatives bind and are capable to alter tau aggregation pathways, resulting in the formation of tau structures with decreased toxicity. Conclusions: Further investigations on the capability of curcumin analogs to target and modulate toxic oligomeric tau strains associated with different neurodegenerative tauopathies will deliver compelling evidence moving the tau field forward. Curcumin analogs could aid both in the development of novel therapeutic approaches for AD and other tauopathies as well as imaging agents able to detect toxic tau oligomeric strains in the early stages of the disease. P4-407
REGIONAL DIFFERENCES IN THE TRANSIENT EQUILIBRIUM OF [18F] AV-1451 AND THEIR IMPACT ON TISSUE UPTAKE RATIOS
Kerstin Heurling1, Ruben Smith2,3, Andreas Hahn4, Olof Strandberg2, Jonas J€ogi3, Tomas Ohlsson3, Michael Sch€oll1, Oskar Hansson5,6, 1 University of Gothenburg, Gothenburg, Sweden; 2Lund University, Lund, Sweden; 3Sk ane University Hospital, Lund, Sweden; 4Medical University of Vienna, Vienna, Austria; 5Sk ane University Hospital, Malm€o, Sweden; 6 Lund University, Malm€o, Sweden. Contact e-mail: [email protected] Background: Absolute quantification of PET ligand uptake requires true equilibrium between tissue and plasma radioactivity. While this can only be achieved using continuous ligand infusion, a ”transient equilibrium” (TrEq) at the maximum specific binding can be identified using a bolus infusion protocol. Theoretically, the TrEq could be used to estimate the specific binding of the tracer, described as the tissue ratio of specific and nondisplaceable binding. Deviation from TrEq when estimating tissue ratios, causes over- or underestimation of the binding, and
P4-405
Poster Presentations: Wednesday, July 19, 2017
MONOAMINERGIC CORRELATES OF DISINHIBITED BEHAVIOURS IN THE NOVEL TAU58/4 TRANSGENIC MOUSE MODEL FOR TAUOPATHY
Femke Valkenburg1,2, Debby Van Dam1,2,3, Yannick Vermeiren1,2,3, Tony Aerts1,2, Peter Paul De Deyn1,2,3,4,5, 1University of Antwerp, Wilrijk, Belgium; 2Institute Born-Bunge, Wilrijk, Belgium; 3University of Groningen, Groningen, Netherlands; 4Memory Clinic of Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; 5 Biobank, Institute Born-Bunge, Wilrijk, Belgium. Contact e-mail: Femke. [email protected] Background: Tauopathies, such as frontotemporal dementia (FTD), are characterized by both memory and behavioural alterations. Especially patients with the behavioural variant of FTD exhibit disinhibited behaviours, for instance aggression and sexual disinhibition. These disturbances have been linked with altered neurotransmitter systems including, most prominently, alterations in dopaminergic and serotonergic systems. We aimed to investigate whether neurochemical correlates of disinhibited behaviours are observable in the novel transgenic Tau58/4 tauopathy mouse model, similar to observations in patients. Thereby, we hope to enable future in-depth investigation of the underlying pathologic mechanisms. Methods: Heterozygous (HET) Tau58/4 mice (C57BL6/J background with P301S mutation in exon 10) and age-matched control wild-type (WT) littermates, aged 3 (HET n¼6; WT n¼8) or 9 months (HET n¼4; WT n¼4), underwent behavioural testing related to aggression (aggression-induced resident-intruder test) and sexual disinhibition (ovariectomized, hormonally primed stimulus females). Subsequently, levels of serotonin (5-HT), dopamine and (nor)epinephrine ((N)E), as well as their respective metabolites (5-hydroxy-3-indoleacetic acid (5HIAA), 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylglycol) were quantified in regionally dissected brain samples by means of an optimised ultra-high performance liquid chromatography system, coupled with electrochemical detection. Results: Preliminary results indicated that HET animals aged 3 and 9 months exhibited more offensive behaviours (i.e. sniffing, aggressive grooming; 3 months p<0.001; 9 months p¼0.021), but less defensive behaviours (upright posture; 3 months p<0.001; 9 months p¼0.021) than WT controls. So far, we did not find significant differences in neurotransmitter composition between HET and WT animals of the same age with respect to frontal cortex (FC) and (hypo)thalamus ((h)THAL), apart from an agedependent neurochemical increase in the FC (NA p¼0.007, 5-HIAA p¼0.027 and 5-HT p¼0.027) and (h)THAL (NA p¼0.027 and 5-HIAA p¼0.011) of the WT group. Conclusions: Tau58/4 mice exhibited more aggressive behaviours and less defensive behaviours at both early and advanced stages of tauopathy compared with controls, indicating an increase in disinhibitionlike behaviours. Preliminary investigations in FC and (h)THAL, however, were not significant, possibly due to relatively small sample sizes. Results of additional age groups and behavioural experiments, as well as neurochemical results of extra analysed brain regions will be presented during the AAIC 2017 conference. P4-406
INVESTIGATING THE POTENTIAL OF NOVEL CURCUMIN DERIVATIVES IN TARGETING AND MODULATING TOXIC TAU OLIGOMERIC STRAINS
Filippa Lo Cascio1,2, Urmi Sengupta1, Antonio Palumbo Piccionello2, Andrea Pace2, Claudia Campanella2, Celeste Caruso Bavisotto2,
Rakez Kayed1, 1University of Texas Medical Branch, Galveston, TX, USA; University of Palermo, Palermo, Italy. Contact e-mail: [email protected]
2
Background: Tauopathies are devastating age-related neurodegenerative disorders, characterized by the pathological aggregation and accumulation of the microtubule-associated protein tau and its subsequent deposition in different aggregated forms, including neurofibrillary tangles (NFTs). Recent research suggest that NFTs are the least toxic form of tau aggregates. However, the smaller, dynamic and soluble tau oligomers have been shown to be more toxic and efficient seeds for the propagation of pathology as compared to NFTs. Tau oligomers are a heterogeneous group of biophysically and conformationally distinct tau multimers that manifest in many different conformations, termed tau oligomeric strains. Due to the dynamic nature of these strains, studies focusing on the mechanisms underlying their formation and characteristics are challenging. Importantly, different tau oligomeric strains could explain how the aggregation of the same protein causes different diseases, progression rates and phenotypes even between individuals within the same disorder. Thus, depleting the disease-relevant structures by using small molecules could be a powerful therapeutic strategy that targets toxicity regardless of other factors involved in the formation of tau oligomeric strains. Methods: Herein we screened newly synthetized curcumin-like compounds to target and modulate tau oligomeric strains toxicity. Modulating their conformations through the use of novel curcumin derivatives could be useful for the prevention of tau oligomers formation and toxicity. We used in vitro techniques such as Western Blot and direct ELISA as well as biophysical assays to characterize tau oligomeric strains and their reactivity with tau oligomer specific polyclonal and monoclonal antibodies, T22 and TOMA respectively, in the presence and absence of curcumin derivatives. Results: Interestingly, novel curcumin derivatives bind and are capable to alter tau aggregation pathways, resulting in the formation of tau structures with decreased toxicity. Conclusions: Further investigations on the capability of curcumin analogs to target and modulate toxic oligomeric tau strains associated with different neurodegenerative tauopathies will deliver compelling evidence moving the tau field forward. Curcumin analogs could aid both in the development of novel therapeutic approaches for AD and other tauopathies as well as imaging agents able to detect toxic tau oligomeric strains in the early stages of the disease. P4-407
REGIONAL DIFFERENCES IN THE TRANSIENT EQUILIBRIUM OF [18F] AV-1451 AND THEIR IMPACT ON TISSUE UPTAKE RATIOS
Kerstin Heurling1, Ruben Smith2,3, Andreas Hahn4, Olof Strandberg2, Jonas J€ogi3, Tomas Ohlsson3, Michael Sch€oll1, Oskar Hansson5,6, 1 University of Gothenburg, Gothenburg, Sweden; 2Lund University, Lund, Sweden; 3Sk ane University Hospital, Lund, Sweden; 4Medical University of Vienna, Vienna, Austria; 5Sk ane University Hospital, Malm€o, Sweden; 6 Lund University, Malm€o, Sweden. Contact e-mail: [email protected] Background: Absolute quantification of PET ligand uptake requires true equilibrium between tissue and plasma radioactivity. While this can only be achieved using continuous ligand infusion, a ”transient equilibrium” (TrEq) at the maximum specific binding can be identified using a bolus infusion protocol. Theoretically, the TrEq could be used to estimate the specific binding of the tracer, described as the tissue ratio of specific and nondisplaceable binding. Deviation from TrEq when estimating tissue ratios, causes over- or underestimation of the binding, and