AAIC 2025
What is Touchscreen Cognition?
Featured Research Session
Advancing Translational Success By Enhancing Predictive Validity In Neurodegenerative Diseases
Thursday, July 31 | 10:00am – 11:30am | Room 718
An opportunity to learn state of the art approaches in target identification and validation and examples on how to improve the predictive value of preclinical testing for successful treatments in humans.
Chairs |
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| Marco A. M. Prado, PhD Western University, London, ON, CA |
Vania F. Prado, PhD, DDS Western University, London, ON, CA |
Presenting Authors and Subjects |
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| Stacey J. Sukof Rizzo PhD, University of Pittsburgh, Pittsburgh, PA, USA |
Predicting differential effects of sex on therapeutic benefit and limitations in Alzheimer’s disease drug development using animal models |
| Anoosha Attaran PhD, Western University, London, ON, CA |
Combining humanized mice, neurochemical, imaging, and cognitive biomarkers for drug discovery in mice |
| Neil R. Cashman MD, University of British Columbia, Vancouver, BC, and ProMIS Neurosciences, Toronto, ON, CA |
Protein misfolding-specific epitope identification for passive and active immunotherapy of neurodegenerative diseases |
| Frank M. Longo MD, PhD, Stanford Medicine, Stanford, CA, and PharmatrophiX, San Francisco, CA, USA |
p75 neurotrophin receptor: a prototype therapeutic target modulating fundamental mechanisms of degeneration and glial function in Alzheimer’s and related dementias |
Poster Information
Sunday, July 27
The Multifactorial Impact of ApoE4 on Alzheimer’s Pathology and Cognitive Decline
Presenter: Aya Arrar
Poster # 105101
| Authors: Aya Arrar, BSc, Madison R Longmuir, MSc, Kate M. Onuska, BSc, Bryan Lung, Scheila Schmidt, PhD, Amr Eed, PhD, Kellly Summers, PhD, Arash Salahinejad, PhD, Ravi S. Menon, PhD, Ali R. Khan, PhD, Lisa M Saksida, PhD, Timothy J Bussey, PhD, Tallulah S Andrews, PhD, Taylor W Schmitz, PhD, Vania F Prado, PhD and Marco AM Prado, PhD |
| Background: Apolipoprotein E (ApoE) isoforms differentially regulate Aβ and tau pathology in Alzheimer’s disease (AD). However, most preclinical models do not recapitulate the combined impact of Aβ, tau, and ApoE on cognitive function and disease progression. To overcome this, we developed new mouse models harbouring humanized variants of the ApoE genotypes (ApoE3, ApoE4), hApp (AppWT, AppNL or AppNL-F) and hMAPT (tau), and evaluated whether their interactions influence cognition, brain structure, and pathological load. |
| Methods: Methods used include single nuclei RNA sequencing (snRNAseq), magnetic resonance imaging (MRI), immunofluorescence microscopy, ELISAs, and Western Blotting. Attentional function was assessed using the cross-species Continuous Performance Task, an automated touchscreen test. |
| Results: Biochemical and immunofluorescence analyses confirm that ApoE genotype interacts with both Aβ and tau to drive distinct pathogenic trajectories. At 6 months, AppNL-F/ApoE4 mice exhibit higher cortical levels of insoluble Aβ42 compared to their ApoE3 counterparts, indicating that ApoE4 accelerates amyloidogenic processes. This trend persists at 9 and 12 months, where AppNL-F/ApoE4 mice show increased insoluble Aβ42 levels, plaque burden and plaque size compared to AppNL-F/ApoE3 mice. Additionally, cortical levels of soluble and insoluble total tau are elevated in AppNL-F/ApoE4 mice relative to AppNL-F /ApoE3 mice at 9 and 16 months, respectively. MRI reveals reduced grey matter volume in frontocortical regions of 6-month-old AppNL-F/ApoE4 mice compared to AppNL/ApoE3 mice. snRNA-seq confirms a reduction in cortical excitatory neurons, and an upregulation of gliosis in AppNL-F/ApoE4 mice. Finally, AppNL-F/ApoE4 mice exhibit attentional deficits on CPT as early as 6 months, with these impairments persisting at 9 and 12 months relative to AppNL-F/ApoE3 mice. Pathology was negligible at all timepoints in AppNL (ApoE3 and ApoE4) and AppWT mice, suggesting that Aβ toxicity drives the pathogenic interactions with ApoE. |
| Conclusions: These findings highlight the multifactorial impact of ApoE4 in AD, demonstrating that humanized AppNL-F/MAPT/ApoE4 mice exhibit biochemical and imaging biomarkers of pathology and a time course of neurodegeneration and cognitive dysfunction that reproduces a human-like phenotype of late onset AD. This work underscores the value of combining these novel mouse models with translational imaging and cognitive biomarkers for understanding the relationship between pathophysiology and high-level cognitive function. |
STIP1 Knockout Mitigates Disease Progression in a Synucleinopathy Mouse Model: A Multimodal Behavioral and Neuroimaging Study
Presenter: Sara Touj
Poster # 106256
| Authors: S. Touj, V. Novikov, M. Malvankar, P. Rodriguez, A. Brandt, J. Park, S. Tullo, D. Gallino, G. A. Devenyi, T. Bussey, L. Saksida, R. S. Menon, M. Prado and M. M. Chakravarty |
| Background: Synucleinopathies, including Parkinson’s disease (PD), are characterized by misfolded alpha-synuclein (αSyn) accumulation, leading to neurodegeneration, motor dysfunction, and cognitive impairments. Normally, Hsp90 helps clear misfolded proteins, but under proteostatic stress, the chaperone network forms an epichaperome, stabilizing toxic aggregates and worsening disease progression. STIP1 (Stress-Inducible Phosphoprotein 1), a key Hsp90 co-chaperone, facilitates αSyn aggregation and stabilizes the epichaperome, promoting neurotoxicity. Understanding its role in synucleinopathies may help identify novel therapeutic targets. This study investigates tamoxifen-inducible conditional STIP1 knockout (STIP1Fx/Cre+) effects on disease progression in an αSyn mouse model, using behavioral and neuroimaging assessments. By examining cognitive outcomes alongside neurodegeneration trajectories, this work aims to determine whether disrupting the epichaperome could serve as a viable strategy for disease modification. |
| Methods: M83 transgenic mice expressing human A53T αSyn were crossed with tamoxifen-inducible CreER mice to generate STIP1Fx/Cre+ and STIP1Fx/Cre− littermates. At 11 weeks, mice received unilateral αSyn preformed fibrils (PFFs) injections into the right dorsal striatum to seed pathology. One week post-surgery, mice were administered tamoxifen for five consecutive days to induce STIP1 knockout. Mice underwent touchscreen-based cognitive testing (Pairwise Visual Discrimination Reversal). We prioritized reproducibility of the Touchscreen experiments by conducting them both at McGill and Western University. T1-weighted magnetic resonance images (MRI; 100 μm³ voxels, Bruker 7T) were acquired at -7 and 90 days post-injection (dpi). Deformation-based morphometry (DBM) was used to assess voxel-wise volumetric changes longitudinally. Linear mixed-effects models analyzed genotype by time interactions for behavioral and MRI data. |
| Results: STIP1Fx/Cre+ mice showed a significant genotype-by-day interaction (β = 1.94, p = 0.001) in touchscreen reversal, improving faster than STIP1Fx/Cre- mice (Fig. 1). This suggests enhanced cognitive flexibility, replicated across sites. MRI DBM analysis revealed that Cre+ mice exhibited progressive volume increases in the thalamus, motor cortex, anterior olfactory nucleus (AON), and reticular nucleus, while STIP1Fx/Cre- mice showed progressive atrophy (Fig. 2). This suggests STIP1 knockout may influence neurodegeneration trajectories in synucleinopathy progression. |
| Conclusions: This study provides evidence that STIP1 depletion alters disease progression, with STIP1Fx/Cre+ mice showing better behavioral outcomes and distinct neuroimaging trajectories. While MRI results indicate region-specific volumetric differences, these findings remain preliminary. Increasing sample size and histological validation will further clarify STIP1’s role. By improving our understanding of STIP1’s function, this study contributes to identifying novel therapeutic targets for αSyn-driven neurodegeneration. |
Monday, July 28
Evaluating the Efficacy and Risks of Early Lecanemab Treatment in APOE4 Humanized Alzheimer’s Disease Mouse Models
Presenter: Arash Salahinejad
Poster # 102371
| Authors: Arash Salahinejad, PhD, Amr Eed, PhD, Mohammad H Alipour, Kellly Summers, PhD, Kate M. Onuska, BSc, Luke Smolders, Ebrima Gibbs, Czarina Evangelista, PhD, Lisa M Saksida, PhD, Timothy J Bussey, PhD, Neil R Cashman, Johanne Kaplan, PhD, Scott Napper, Taylor Schmitz, Vania F Prado, PhD, Ravi S. Menon and Marco AM Prado, PhD |
| Background: Alzheimer’s disease (AD) is the leading cause of dementia. AD disproportionately affects APOE4 carriers, who experience accelerated amyloid β (Aβ) accumulation, including cerebral amyloid angiopathy (CAA). While monoclonal antibodies (mAbs) like lecanemab reduce amyloid plaques, their use is complicated by amyloid-related imaging abnormalities (ARIA-likely related to brain bleeds), particularly in APOE4 carriers. Lecanemab, a humanized mAb targeting Aβ protofibrils, but still poses an enhanced risk for APOE4 carriers. This study explores whether early lecanemab treatment can reduce the risk of microbleeds and prevent cognitive deficits as well as brain atrophy in APOE4 humanized AD mouse models. |
| Methods: Advanced AD mouse models with humanized APP (hApp), Tau (hMAPT), and APOE3/APOE4 genes were used. The murine version of lecanemab (mAb158) was synthesized and shown to target synthetic Aβ oligomers and pre-fibrillar amyloid in these models. Starting at 3 months of age, hAppNL-F-hMAPT-APOE4 and hAppNL-F-hMAPT-APOE3 mice received mAb158 (20 mg/kg weekly for 26 weeks) or vehicle (PBS). Cognitive performance was assessed at 6, 9, and 12 months using a touchscreen-based Continuous Performance Test (CPT) to assess attention. At study end, brain tissues were analyzed via light-sheet microscopy, immunohistochemistry, Prussian Blue staining, and ELISA to evaluate plaques, amyloid deposits, microbleeds, and Aβ levels. |
| Results: Immunohistochemistry and light-sheet microscopy revealed significant amyloid accumulation in the brain and blood vessels of hAppNL-F-hMAPT-APOE4 mice, from 6 months of age onward, compared to hAppNL-F-hMAPT-APOE3. In the mAb158 treated mice, insoluble Aβ accumulation was negligible in both genotypes at 9 months of age and significantly reduced at 15 months of age in hAppNL-F-hMAPT-APOE4 mice compared to vehicle. hAppNL-F-hMAPT-APOE4 mice showed CPT deficits starting at 6 months under vehicle and mAb158, with no difference in performance between treatment groups. Preliminary analyses suggest mAb158 causes microhemorrhages. |
| Conclusions: Early mAb158 treatment reduces key Alzheimer’s disease pathology but fails to prevent attention deficits in hAppNL-F-hMAPT-APOE4 mice and may increase microbleeds in this vulnerable group. By combining new generation mouse models of genetic AD risk with translational cognitive and imaging biomarkers, we propose a preclinical platform to better predict the safety and efficacy of monoclonal antibody treatments. |
Apolipoprotein E (ApoE) 4 exacerbates pattern separation deficits and amyloid pathology in a combined humanized knock-in Apolipoprotein E, Amyloid, and Tau model of Alzheimer’s Disease
Presenter: Ariel Batallán Burrowes
Poster # 99794
| Authors: Ariel A Batallán Burrowes, PhD, Madison R Longmuir, MSc, Aya Arrar, BSc, Beatriz G Muratori, PhD, Suzete M Cerutti, PhD, Lisa M Saksida, PhD, Timothy J Bussey, PhD, Taylor W Schmitz, PhD, Marco AM Prado, PhD and Vania F Prado, PhD |
| Background: Cognitive deficits in Alzheimer’s Disease (AD) are attributed to neuronal network disruptions associated with amyloid β and hyperphosphorylated tau aggregates. Pattern separation, the ability to store and differentiate between similar experiences, is linked to hippocampal function. Pattern separation shows increasing impairment with AD progression. Apolipoprotein E (ApoE) 4 is a significant genetic risk factor for AD, associated with earlier onset, more severe pathology, and cognitive deficits. It is unclear how ApoE4 may interact with AD pathology to affect hippocampal function and pattern separation. This study uses humanized mouse models combining ApoE (3 or 4), App (App, AppNL, AppNL-F), and MAPT (tau) to evaluate the interaction of these factors on pattern separation and amyloid pathology. |
| Methods: Pattern separation was assessed using the automated touchscreen location discrimination (LD) task at ages 6, 9, 12, and 16 months in both male and female mice. Hippocampal amyloid pathology was quantified at the same timepoints using biochemical and immunofluorescence. |
| Results: Whereas AppApoE3 and ApoE4 mice presented no difference in LD performance at 6 months of age, AppNLApoE4 and AppNL-FApoE4 mice demonstrated poorer performance than their ApoE3 counterparts at all ages. When comparing AppNL and AppNL-F groups, AppNL-FApoE4 mice exhibited the poorest performance in comparison to the other groups at all ages. App mice showed no signs of amyloid pathology. AppNLApoE3 and AppNLApoE4 mice showed no significant difference in insoluble Aβ42, and no plaques were detected. In contrast, AppNL-FApoE4 mice displayed increased Aβ42 concentrations compared to AppNL-FApoE3, and also presented increased plaque pathology up to 16 months of age. |
| Conclusions: These results suggest even minor changes in amyloid processing (in AppNL mice) seem to synergize with ApoE4 as a driving mechanism of pattern separation deficits, detectable as early as 6 months old. This effect seems to be independent of insoluble amyloid accumulation, which was significantly increased in the hippocampus only after 9 months. Ongoing work examines whether soluble amyloid oligomers and ApoE4’s direct impact on neurogenesis contribute to the pattern separation deficits. Nonetheless, we observed a reproducible deficit in LD performance in these mice compatible with early pattern separation deficits. |
Reduced cholinergic tone and hippocampal-dependent cognitive impairments in APPNL-F mice
Presenter: Alycia Crooks
Poster # 107535
| Authors: Alycia M Crooks, BSc, Kate M. Onuska, BSc, Taylor W Schmitz, PhD, Lisa M Saksida, PhD, Timothy J Bussey, PhD, Vania F Prado, PhD and Marco AM Prado, PhD |
| Background: The prevailing model of Alzheimer’s disease (AD) proposes that the accumulation of misfolded amyloid-beta (Aβ) peptides drives tau protein hyperphosphorylation and neuroinflammation, leading to neurodegeneration and cognitive decline. However, current therapeutic approaches targeting Aβ show only subtle ehects on cognitive deficits. Interestingly, the loss of cholinergic neurons of the basal forebrain precedes and predicts pathology and neurodegeneration in AD. The vesicular acetylcholine transporter (VAChT), a key regulator of cholinergic signalling, functions at the presynaptic terminal by loading acetylcholine (ACh) into vesicles for secretion. Notably, VAChT expression is significantly reduced in AD brains, with changes observed early in disease progression. Whether these early changes in cholinergic synaptic function contribute to hippocampal dysfunction remains unclear. Using the APPNL-F mouse model of AD, which expresses humanized Aβ with familial AD mutations, this study investigates the interplay between cholinergic signalling and hippocampal-dependent cognitive function. |
| Methods: ACh signalling was recorded using fibre photometry and the GRABACh sensor in the hippocampal CA1 region of freely behaving APPNL-F and control mice performing the Trial-Unique delayed Nonmatching-to-Location (TUNL) task. This task assesses spatial working memory, a cognitive domain impaired in AD. Large and small separation windows were used to challenge spatial discrimination. |
| Results: Analysis of VAChT levels have shown some dynamic regulation, but with aging VAChT levels decreased substantially. Recordings of ACh dynamics in the hippocampal CA1 region revealed behaviour-associated changes, particularly during screen approaches, touches, and predominantly reward responses. Cholinergic tone decreases substantially in response to reward, demonstrating tonic ACh signalling that can change in response to specific stimuli. Young APPNL-F mice, tested before substantial plaque accumulation, exhibit deficits in spatial working memory during challenging conditions, which associated with reduced cholinergic responses. The deficit in cholinergic tone in APPNL-F mice closely mirrors the cholinergic dysfunction observed in the forebrain VAChT knock-out mice, which showed pronounced impairments in learning, memory, and ACh signalling during the TUNL task. |
| Conclusions: These findings highlight the role of early deficits in cholinergic synaptic function associated with spatial memory impairments before overt pathology in APPNLF mice. Future experiments aim to develop strategies to rescue memory and cholinergic tone dysfunction. |
Translational Cognitive Biomarkers for Preclinical Drug Testing in Neurodegenerative Disease
Presenter: Rodrigo Sandoval
Poster # 103517
| Authors: Rodrigo Sandoval, Vladislav Novikov, Anoosha Attaran, Mohammad-Hossein Tabatabaei, Amr Eed, Matthew Cowan, Man Ching Yau, Yasmien Abduldayem, Sahil Sharma, Wen Luo, Irina Shlaifer, Czarina Evangelista, Thomas M. Durcan, Edward A. Fon, Ravi S. Menon, Gabriela Chiosis, Timothy J. Bussey, Lisa M. Saksida, M. Mallar Chakravarty, Vania F. Prado, and Marco A.M. Prado |
| Background: Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the accumulation of misfolded proteins, including amyloid-β, tau, and alpha-synuclein (a-Syn). Despite extensive research, no effective disease-modifying therapies exist. A major barrier to drug development is the poor translatability of animal models and the lack of biomarkers with predictive power for clinical efficacy. Higher-order cognitive deficits, such as impaired reversal learning, are observed in patients with synucleinopathies, suggesting that cognitive biomarkers could be valuable in preclinical drug testing. This study evaluates whether touchscreen-based cognitive testing enhances the predictive validity of preclinical drug testing. We assessed PU-AD, an HSP90 epichaperome disruptor targeting the abnormal chaperone network implicated in protein misfolding disorders, and a mouse version of Cinpanemab, an anti-a-Syn antibody that recently failed in clinical trials, despite initial positive results in animal models. |
| Methods: Hemizygous M83 transgenic mice were intracerebrally injected with preformed fibrils (PFFs) to model synucleinopathy-related neurodegeneration. Mice underwent cognitive assessment using the Pairwise Visual Discrimination and Reversal (PVD-R) touchscreen task, a highly translational measure of cognitive flexibility sensitive to a-Syn toxicity. PU-AD and Cinpanemab were administered intraperitoneally post-PFF injection. Drug doses matched previous animal model studies. Motor performance was assessed with grip strength, rotarod, and wire hang tests. MRI was used to detect brain atrophy. Immunohistochemical and biochemical analyses evaluated a-Syn pathology and neuroinflammation. |
| Results: M83/PFF-injected mice showed significant reversal learning deficits earlier than motor deficits. Pharmacokinetic analysis confirmed PU-AD reached brain concentrations comparable to those in other models. PU-AD treatment rescued cognitive and motor impairments, suggesting broad neuroprotective effects. In contrast, Cinpanemab-treated mice showed no improvements in cognition and preliminary data suggest no improvements in motor symptoms. Ongoing experiments are evaluating pathology and brain atrophy. |
| Conclusions: The lack of Cinpanemab efficacy in our pre-clinical testing pipeline aligns with clinical trial results. The effectiveness of PU-AD in reducing both cognitive and motor impairments suggests it may have broad therapeutic potential in synucleinopathies. We suggest that touchscreen-based cognitive testing enhances the predictive validity of preclinical drug evaluation. |
Tau pathology in triple knock-in mouse model of Alzheimer's Disease Expressing APOE3 and APOE4
Presenter: Jamie Fournier
Poster # 101626
| Authors: Jamie L Fournier, BSc, Aya Arrar, BSc, Madison R Longmuir, MSc, Taylor W. Schmitz, PhD, Lisa M Saksida, PhD, Timothy J Bussey, PhD, Vania F Prado, PhD and Marco AM Prado, PhD |
| Background: Tau is a microtubule stabilizing protein that becomes dysfunctional during the course of Alzheimer’s Disease. Previous research has shown that individually amyloid and APOE4 have the potential to increase tau phosphorylation and worsen tau pathology in tau mutant models of tauopathy. However, whether both amyloid and APOE4 can further contribute to tau dysfunction in mouse models that more faithfully reflect the levels of tau in humans is unknown. We developed mouse models with a combination of incorporated humanized knock-in variants of hMAPT, AppNL and AppNL-F and APOE 3 or APOE 4 genotypes. |
| Methods: Biochemical and imaging techniques including immunofluorescence microscopy and Western Blots were performed for phosphorylated tau at the Serine 202/Threonine 205 sites (AT8) and total tau. Visuospatial learning and memory were assessed using the Paired Associates Learning (PAL) task, an automated touchscreen task. |
| Results: Our preliminary results indicated that tau protein phosphorylated at the Serine 202/Threonine 205 phosphorylation site is detected in in both male and female mice in a genotype dependent manner. Aging, expression of App NL-F and APOE4 increased tau phosphorylation. Insoluble total tau was found predominantly in aged mice (18 months) and was worse in APOE4 expressing individuals. All the antibodies used detected no signal in tissue from tau knockout mice confirming the results are a consequence of changes in tau. Preliminary results indicate that 12-month old App NL and App NL-F mice (ApoE3 and ApoE4) were able to learn the PAL task to 70% accuracy. There were no genotype-dependent differences in performance. |
| Conclusions: The results of this project demonstrate that tau pathology markers appear to increase as a function of age, APOE4 and the ability to accumulate insoluble Abeta and plaques. These results agree with the notion that amyloid and APOE4 can increase tau markers even in less aggressive animal models without tau overexpression or mutations. Our findings also suggest that there are no genotype-dependent differences in learning and memory in the PAL task at early ages, despite these mice presenting other cognitive deficits at that stage. |
Tuesday, July 29
Pleiotropic effects of Apolipoprotein (ApoE) 4 on executive function in mice and humans
Presenter: Madison Longmuir
Poster # 99431
| Authors: Madison Longmuir, Aya Arrar, Kate M Onuska, R. Nathan Spreng, Daniel Palmer, Tim J. Bussey, Lisa M. Saksida, Vania F. Prado, Marco A.M. Prado, Taylor W. Schmitz, PREVENT-AD Research Group |
| Background: ApoE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Compared to ApoE4 noncarriers (ApoE4-), ApoE4 carriers (ApoE4+) exhibit earlier onset and more rapid progression of memory impairment. However, separate lines of work have suggested the opposite pattern in other cognitive domains: ApoE4+ individuals exhibit superior executive function compared to ApoE4-, but this advantage decreases with age. The antagonistic pleiotropy hypothesis proposes that ApoE4 may therefore confer advantages to brain function at earlier ages, but these advantages become detrimental later in life. To investigate this hypothesis, we took a cross-species translational approach focusing on cognitively unimpaired human adult ApoE4+ and ApoE4- within the age range 65-80 years, in combination with knock-in mouse models that express humanized wild-type App, MAPT, and ApoE3/4 genes. |
| Methods: To quantify executive function, we utilized the cross-species touchscreen-based Continuous Performance Task (CPT) to evaluate selective attention. Human participants were drawn from the PREVENT-AD program at the Douglas Research Centre, with testing conducted on MS SurfacePros. Mice performed the same task using an operant chamber platform. |
| Results: Behavioural results suggest that ApoE4 facilitates attentional processes in both older adult and mouse ApoE4 carriers, as indexed by discrimination performance on the CPT. Further strengthening this translational pattern, we found that the facilitative effect of ApoE4 on CPT was more pronounced in female ApoE4+ of both species. In mice, we examined the ApoE-dependent effects on attention longitudinally (spanning 12 months), finding that the positive effect of ApoE4 was sustained across this interval in females, though it became less robust with age. In contrast, ApoE4 was beneficial in males only during early life. Notably, these effects were observed in the absence of detectable brain pathology. |
| Conclusions: These results support the antagonistic pleiotropy hypothesis, whereby ApoE4 carriership confers greater attentional performance early in life and in the absence of classical AD pathology. This effect is detectable in both sexes but is stronger and more sustained across age in females. All these patterns are conserved across humans and mice, suggesting that this cross-species translational platform is well suited to explore the mechanistic basis of ApoE4 antagonistic pleiotropy as it relates to domain-specific cognitive function. |
Characterization of mouse models of synucleinopathies
Presenter: Latiyah Timothy
Poster # 106153
| Authors: Latiyah Timothy, Vladislav Novikov, Kelly Summers, Thomas M. Durcan, Edward A. Fon, Czarina Evangelista, Ravi S. Menon, Lisa M. Saksida, Timothy J. Bussey, Joel C. Watts,Vania F. Prado, Marco A.M. Prado |
| Background: Synucleinopathies, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are characterized by the aggregation of pathological alpha-synuclein (αSyn). The M83 hemizygous (het) transgenic mouse model has been extensively used to study synucleinopathy after injection of human αSyn preformed fibrils (PFFs). However, similar to other transgenic mouse lines, M83 mice present an aggressive phenotype. To explore alternative models, we first attempted to reproduce the use of wild-type (WT) mice injected with mouse αSyn PFFs. Moreover, we generated new knock-in humanized αSyn mouse models expressing fully human wildtype, PD (A53T) or DLB (E83Q) mutants. |
| Methods: M83 hemizygous mice injected with human PFFs were studied with lightsheet microscopy. WT mice were injected with mouse αSyn PFFs or PBS (control). Cognitive flexibility was evaluated using the Two-Choice Pairwise Visual Discrimination-Reversal (PVD-R) touchscreen task. Motor behavior was assessed with Rotarod, Catwalk gait analysis, wire-hang, grip force, and open field. Phosphorylated αSyn was evaluated using Western-blots and immunofluorescence. Constructs and Humanized mice were generated in collaboration with Cyagen using CRISPR-Cas and homologous recombination. |
| Results: M83 mice showed early cognitive impairments but we also found a disproportional amount of S129-phosphorylated αSyn in the spinal cord, which agrees their extensive motor impairments. Preliminary findings indicate no significant differences in cognitive performance between mouse PFF-injected and control mice in the PVD-R task. Additionally, our analyses revealed little to no αSyn pathology in WT mice. Only male WT PFF-injected mice exhibited mild motor deficits in rotarod and wire hang at approximately 8 months post-injection, despite showing minimal αSyn pathology. Western-blot analyses confirmed that human αSyn is expressed in heterozygous humanized mouse models in similar levels its mouse counterpart. Phosphorylated αSyn was also detected in the RIPA soluble fraction in the mutant mice. |
| Conclusions: Our experiments indicate limitations of the M83 and WT αSyn PFF models. Given these findings, we will focus on humanized WT, A53T, and E83Q SNCA models. These models are expected to offer more physiologically relevant αSyn expression and enhanced reliability for studying synucleinopathies. We anticipate that they may advance our understanding of disease progression and the identification of potential therapeutic targets. |
Wednesday, July 30
Resistance exercise improves working memory, but not set shifting in older adults at risk for diabetes
Presenter: Olivia Ghosh-Swaby
Poster # 108823
| Authors: Olivia R Ghosh-Swaby, PhD, Jennifer Hanna Al-Shaikh, MSc, BA, Jane Thornton, PhD, MD, Ali R. Khan, PhD, Daniel Palmer, PhD, Paul A Sheppard, PhD, Joyla A Furiano, PhD, Teresa Liu-Ambrose, PhD, PT, Timothy J Bussey, PhD, Lisa M Saksida, PhD, and Lindsay S Nagamatsu, PhD |
| Background: Older adults at risk for type 2 diabetes (T2D) experience cognitive decline and brain health abnormalities, highlighting the need for early interventions. Resistance exercise training (RT) holds promise as a strategy to improve executive function, mitigate T2D risk factors, and support neuroplasticity, especially in aging. This study evaluated the effects of a 6-month RT intervention compared to balance-and-tone (BAT; active control) exercise on cognitive outcomes, particularly set shifting, physiological measures, and biomarkers in older adults at risk for T2D. |
| Methods: Sixty community-dwelling adults (aged 60-80 years) with risk factors for diabetes (body mass index :::25, fasting glucose 6.1-7.0 mmol/L, or CANRISK score :::21) were randomized to twice-weekly RT or BAT classes. Primary outcomes included set-shifting performance and cognitive flexibility (Trail Making Test [TMT] Part B; TMT-B minus TMT-A). Secondary outcomes encompassed working memory (Digit Span Backward), global cognitive scores (Montreal Cognitive Assessment (MoCA), Alzheimer’s Disease Assessment Scale [ADAS-Cog-11 ]) and associative learning using a novel Bussey-Saksida touchscreen cognitive task nearly identical to its rodent version. Additionally, Measures of mobility, fitness, glycemic control, and biomarkers were examined (brain derived neurotrophic factor, BDNF, insulin growth factor-1, IGF-1). An ANCOVA and repeated measures ANOVA was used to assess intervention effects on outcomes at endpoint and over time, respectively, with baseline performance and adherence as covariates (p<0.050 significant). |
| Results: RT improved working memory (Digit Span Backward; p = 0.024) compared to BAT at endpoint, with a trend toward enhanced cognitive flexibility over time (TMT-B minus TMT-A; p = 0.049). No significant differences were observed in global cognitive scores (MoCA, ADAS-Cog-11 ). Bussey-Saksida touchscreen tasks were adapted and validated for human use. Participants showed low accuracy on paired associative learning (54-64% ± 4% accuracy), irrespective of training group. RT improved lower body strength over time (p=0.036), with no changes in glycemic levels. IGF-1 levels decreased in the RT group (p = 0.037), with no changes in BDNF. |
| Conclusions: Resistance exercise training offers targeted cognitive benefits in older adults at risk for diabetes, suggesting its potential as an intervention to address both T2D risk factors and cognitive decline. Further studies should explore long-term impacts on brain structure and function. |