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Explore the most appropriate preclinical strategy for evaluating your therapeutic candidate in CNS disorders.
Measurement of cognitive performance
Preclinical and translational models for assessing memory, cognition and behavioral performance.
Soluble Amyloid-β Oligomer-Induced Memory Deficits in the Mouse
Description
Soluble amyloid-β oligomers (Aβos) are injected intracerebrally in mice, inducing neurodegeneration and the impairment of memory.
Method
Male C57BL/6J mice receive intraventricular (icv) injection of purified, soluble Aβos (1-42), previously validated for their ability to show the proper aggregation states and their efficacy in inducing memory impairment in the same species. Intrahippocampal administration is also possible. A scrambled Aβ peptide is used as control. We have found that a single icv injection of Aβos is sufficient to induce memory deficits and neuropathological changes within about 15 days. Test compounds, aimed at reversing or preventing the Aβos-induced pathology, can be administered systemically via the intraperitoneal, subcutaneous or oral routes.
Endpoints
Memory function is measured using the two-trial discrimination task in the Y-maze (spatial recognition memory). An alternative is the novel object recognition task (or its spatial version which particularly taxes hippocampal function).
Postmortem brain analysis includes:
- Western Blots for Aβ(1-42), Tau (phosphorylated forms of Tau and Tau on the same blot), synaptic markers (e.g. synaptophysin and PSD-95), gliosis (GFAP) and microglial activation (ED1) and apoptosis (Caspase 3).
- Markers of neuronal death can also be used (Cresyl violet/DAPI/Hoechst staining).
References
O. Nicole, S. Hadzibegovic, J. Gajda, B. Bontempi, T. Bem, P. Meyrand, Soluble amyloid beta oligomers block the learning-induced increase in hippocampal sharp wave-ripple rate and impair spatial memory formation. Sci Rep 6, 22728 (2016).
Cognitive Performance in Young and Aged Macaques
Description
Aged animals are ideal for evaluating cognition-enhancing strategies and are particularly relevant for development of cognitive performance enhancers targeting Alzheimer’s disease or mild cognitive impairment (MCI). We have recently shown that this model is superior to rodent models in terms of predicting outcomes from studies of potential cognition enhancing drugs in human Alzheimer’s disease (Schneider et al., 2013).
Method
Cognitive status is quantified in animals of approximately 20 to 25 years of age. This is done using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Many of the CANTAB tests for primates have a direct equivalent in human cognitive testing, thus making the results obtained in primates highly valuable for planning clinical trials in man. Several CANTAB assessment tools are known to be sensitive to age-related cognitive impairment.
Endpoints
Delayed Matching/Non-Matching to Sample. This is a temporal short-term visual memory task with various levels of difficulty, sensitive to mild Alzheimer’s disease.
Paired Associate Learning Task. This is a conditional learning and memory task, which is particularly sensitive to early Alzheimer’s disease.
Discrimination Learning – Long Term Retrieval Task. This is a conditional learning task that assesses the ability to form new long-term memories and their retention over time.
Intra/Extra-Dimensional Set Shift and Visual Discrimination (ID/ED). This is the CANTAB equivalent of the Wisconsin Card-Sorting Test, an executive functioning task that assesses cognitive flexibility, set shifting ability and concept formation. Executive functioning is affected in a variety of neurological and psychiatric disorders.
Object Retrieval Task. This task requires the retrieval of a reward from a 3-dimensional, transparent maze of varying complexity. It tests both cognitive and motor abilities.
The Human Intruder Test (HIT) primarily assesses anxiety and, secondarily, depressive behaviours in monkeys by observing their reactions to a human. The test includes two conditions: an unfamiliar experimenter staring at the animal (a stressful situation) and a familiar experimenter avoiding eye contact (a less stressful situation). The observed behaviours (eye contact, posture, immobility, fear-related grimaces, scratching, yawning, etc.) are used to calculate anxiety and depression scores.
Visual Attention Test (VAT): Visual attention is assessed using a moving stimulus, with analysis of glance and gaze frequency, duration, and intervals between looks across four daily sessions.
References
Castonguay, J. Dufort-Gervais, C. Menard, M. Chatterjee, R. Quirion, B. Bontempi, J. S. Schneider, A. F. T. Arnsten, A. C. Nairn, C. M. Norris, G. Ferland, E. Bezard, P. Gaudreau, P. J. Lombroso, J. Brouillette, The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. Curr Biol 28, 1079-1089 e1074 (2018).
S. Schneider, E. Y. Pioli, Y. Jianzhong, Q. Li, E. Bezard, Effects of memantine and galantamine on cognitive performance in aged rhesus macaques. Neurobiol Aging 34, 1126-1132 (2013).
Scopolamine Model
Description
Scopolamine, an antagonist at the muscarinic acetylcholine receptor, has been shown primarily to impair memory function in humans and non-human primates. This is used as a model of memory failure in Alzheimer’s disease. The specificity of the memory deficits produced by scopolamine may be of particular relevance for the evaluation of new therapeutics designed to ameliorate the cognitive dysfunction associated with Alzheimer’s disease.
Method
Cognitive status is quantified in mature macaques (approximately 7 to 10 years old) using the Cambridge Neuropsychological Test Automated Battery (CANTAB). For details of the specific assessment tools available, see Cognitive Performance in Aged Macaques.
Endpoints
See Cognitive Performance in Aged Macaques.
