In vivo Models of Sporadic Alzheimer's Disease
This page contains the following readouts:
- Y-Maze (prefrontal cortex)
- Morris Water Maze (hippocampus)
- Novel Object Recognition (perirhinal cortex)
- Spacial Recognition Test (hippocampus)
A single intracerebroventricular (icv) injection of amyloid-β oligomers (AβO) in normal mice of various ages induces cognitive defects within few days. In our full cognitive evaluation of the mouse model we investigate induced neurodegeneration in:
- Short term memory (Y-maze)
- Learning (Morris water maze, MWM)
- Long term memory (MWM)
- Memory formation (novel object recognition, NOR)
- Spatial memory (spatial recognition test, SRT)
- Global behavior (Open-field)
Groups of 10 WT mice, or more, are treated by a single icv injection of minute amounts of AβO and investigated for the improvements by symptomatic drug candidates, or for the neuroprotective effects of disease modifying drug candidates. Drug treatments can be preventive, given before AβO treatment, or curative, given after or during AβO treatment. Possible routes of administration are: po, sc, or ip, or once icv or iv.
One possible experimental cycle is performed in a minimum of 14 days, as given below:
Y-Maze Model of Alzheimer's Disease:
Automatic Y-Maze Observation and Evaluation
The Y-maze model is largely established in cognitive investigations and uses the natural behavior of rodents to alternate between choices on subsequent trials. However, such alternation requires short-term memory of the previous choice and attention to the task and is largely dependent on the pre-frontal cortex. Rodents with strong cognitive impairment will show random behavior.
Already four days after the single icv injection of Aβ oligomers (AβO) the mice show significant changes in the Y-maze assay, which persist for up to three month (max. lenght of investigation). The same mice can be investigated on a weekly basis in logitudinal studies:
- Typically reduction of alternation behavior close to the random 50%
- Partially reverted by e.g. Donepezil (Aricept®), a clinically approved cholinesterase inhibitor
Product Sheet “Mouse Y-Maze Assay”, Download PDF, 500 KB
Product Sheet “FAST Symptomatic and Neuroprotection Screen”, Download PDF, 530 KB
Morris Water Maze Model of Sporadic Alzheimer's Disease:
Automatic Observation in MWM
The Morris water maze is another widely accepted cognition model, investigating spatial learning and (long-term) topographical memory, largely dependent on hippocampal function. Mice are trained to find a platform hidden under the opaque water surface in multiple trials. Their learning performance in recalling the platform location is based on visual clues and video recorded. Their learning speed, which is the steadily reduced time from their release into the water until finding the platform, is investigated over multiple days.
For analyzing their long-term memory, the test is repeated multiple days after training: the platform is taken away and the number of crossings over the former platform location, or the time of the first crossing, are used as measures to investigate their long-term memory.
The light blue circle shows the location of the platform. The pool is divided in four quadrants. In yellow, the swimming trajectory of a vehicle injected control mouse is shown. In red, the pathway of an AβO injected mouse is depicted.
Product Sheet “Mouse Full Cognition Enhancement AD Assay”, Download PDF, 510 KB
Novel Object Recognition Model of Sporadic Alzheimer's Disease
The Novel Object Recognition model utilizes the normal behavior of rodents to investigate novel objects for a significantly longer time than known objects, largely dependent on perirhinal cortex function. Mice or rats are icv injected with vehicle or SynAging’s amyloid-β 1-42 oligomer preparation (AβO) on day 0 and can be treated with symptomatic or disease modifying drug candidates before and after that date. The NOR assay can be performed multiple times in longitudinal studies to investigate disease modification after drug wash-out.
On day four, or later, after icv injection, the mice or rats are allowed to explore two identical objects in the acquisition trial. Following a short inter-trial interval, one of the objects is replaced by a novel object. The animals are returned to the arena and the time spent actively exploring each object is recorded. Normal rodents recall the familiar object and will spend significantly more time exploring the novel object. In contrast, AβO treated rodents exhibit clear cognitive impairment and will spend a similar amount of time investigating both the 'familiar' and 'novel' object. This can be transiently reversed with known clinical cognitive enhancers (e.g. donepezil).
This assay has been built-up and validated at SynAging for mice (product sheet below) and rats (graphs above) at a partner site. SynAging will always organize, coordinate and report the evaluation of your test items in this model.
Product Sheet “Mouse NOR Screen”, Download PDF, 480 KB
Spacial Recognition Test (SRT), a Quick Test of Hippocampal Function
Topographical memory (TM) is the ability to recall the contours, design, shape, or structure of a surrounding, and linked to hippocampal function. TM is disrupted during the early stages of Alzheimer’s disease and the SRT is sensitive to drugs used for Alzheimer’s disease treatment.
SynAging uses a two-chamber apparatus for SRT, in which both chambers differ in shape, pattern and color (i.e. are topographically different). The two compartments are connected by a clear Plexiglas corridor. No habituation is necessary. SynAging validated the disruption of TM in the SRT by amyloid-β oligomers (AbO). In comparison to the well established Morris Water-Maze, SRT is also hippocampus-dependent, but does not involve a learning component, making it fast, cost effective and allowing longitudinal studies.
Evaluation of test compound mediated improvement of hippocampal function is performed in the SRT assay. In the figure above, the results are presented for day 15: vehicle injected control mice can differentiate between familiar and novel chamber, whereas AβO-injected mice do not differentiate, as they lost the memory of the familiar chamber. Humanin, co-injected with AβO, can rescue the AβO-induced cognitive decline. This assay can be performed multiple times in longitudinal studies, e.g. to differentiate disease modifying versus symptomatic effects.
Product Sheet “Mouse Spatial Recognition Test”, Download PDF, 450 KB