Motor and Hippocampal Dependent Spatial Learning and Reference Memory Assessment in a Transgenic Rat Model of Alzheimer's Disease with Stroke

Summary

To investigate the co-morbid Alzheimer's disease (AD) and stroke condition in a novel model, three behavior tasks are described that assess both motor control and cognitive behaviors. These tasks include the beam-walk task, cylinder task and Morris water maze.

Abstract

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk factor for AD, stroke has also been implicated as a risk factor and an exacerbating factor. The co-morbidity of stroke and AD results in worsened stroke-related motor control and AD-related cognitive deficits when compared to each condition alone. To model the combined condition of stroke and AD, a novel transgenic rat model of AD, with a mutated form of amyloid precursor protein (a key protein involved in the development of AD) incorporated into its DNA, is given a small unilateral striatal stroke.

For a model with the combination of both stroke and AD, behavioral tests that assess stroke-related motor control, locomotion and AD-related cognitive function must be implemented. The cylinder task involves a cost-efficient, multipurpose apparatus that assesses spontaneous forelimb motor use. In this task, a rat is placed in a cylindrical apparatus, where the rat will spontaneously rear and contact the wall of the cylinder with its forelimbs. These contacts are considered forelimb motor use and quantified during video analysis after testing. Another cost-efficient motor task implemented is the beam-walk task, which assesses forelimb control, hindlimb control and locomotion. This task involves a rat walking across a wooden beam allowing for the assessment of limb motor control through analysis of forelimb slips, hindlimb slips and falls. Assessment of learning and memory is completed with Morris water maze for this behavioral paradigm. The protocol starts with spatial learning, whereby the rat locates a stationary hidden platform. After spatial learning, the platform is removed and both short-term and long-term spatial reference memory is assessed. All three of these tasks are sensitive to behavioral differences and completed within 28 days for this model, making this paradigm time-efficient and cost-efficient.

Introduction

Alzheimer's Disease (AD) is the most prevalent form of dementia in the elderly population and a debilitating neurodegenerative disease. Histopathologically, AD presents itself as amyloid plaques, neurofibrillary tangles and neuronal loss. Amyloid plaques consist primarily of beta-amyloid peptide (Aβ) that has been produced through an altered proteolytic cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase enzymes^1,2,3. The cleavage product, Aβ, deposits in the brain creating pathological amyloid plaques and has toxic effects on the brain that can lead to the characteristic learning impairments and memory loss. A....

Protocol

The appropriate institutional animal ethics committee should approve all of the behavioral procedures prior to starting experimentation. All animal work described here was approved by Western University Animal Use Subcommittee and follows the Canadian Council on Animal Care guidelines. These animal experiments were performed during the light phase.

1. Cylinder Task for Gross Forelimb Motor Assessment

1. Equipment Setup
   1. Acquire a Plexiglas cylinder with a perforated lid that will accommodate the size of the rat used for the experiment. The size of the cylinder should not allow the rat to reach the top when rearing and it should allow fo....

Results

The behavioral tasks described were used to demonstrate the effects of stroke in an APP21 transgenic rat model of Alzheimer's disease. The combination of stroke and the APP21 transgene is expected to result in greater motor deficit in the affected limbs, as well as increased memory deficits.

The cylinder task assessed gross forelimb motor function and is represented as the use of the affected forelimb. Furthermore, the beam-walk.......

Discussion

The combination of stroke and Alzheimer's disease results in very distinct behavioral pathologies that can affect both motor and cognitive function depending on the severity of each condition. Thus, it is necessary to make use of a variety of behavioral tasks to determine the individual contributions of these conditions, as well as give some insight into the combined and potentially interactive effects in the co-morbid condition. The data presented demonstrate three cost-efficient, time-efficient and sensitive behavi.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Cylinder	Western University	Plexiglas Cylinder Cylinder Diameter: 23 cm Cylinder Height: 40 cm Platform Height: 30 cm Mirror Length: 35 cm Mirror Width: 26.5 cm	This was made specifically by Western University Machine Services for our lab. Please contact your own chosen manufacturer to design this product.
Handheld Video Camera	JVC	GZ-E200
Video Camera Tripod	Slik	F163
AM/FM Clock Radio	Sylvania	SCR1388
White Board	Walmart	Width: 71.12 cm Height: 55.88 cm	These can be purchased at any store (i.e. Walmart, University bookstores)
Dry-erase Marker	Expo	Expo Dry-erase Original Marker	These can be purchased at any store (i.e. Walmart, University bookstores)
Wooden Beam	Rona	Plywood Width: 2 cm Length: 100 cm
VWR General Purpose Laboratory Tape	VWR Intl.	89097-920
iMovie '11	Apple Inc.	Version 9.0.9 (1795)	This is the version used in this manuscript, but any other iMovie version or video editing software could be used.
Morris Water Maze Pool with Platform	Stoelting Co.	60136/60035	These are not the exact products used in the video, but these are essentially identical.
Platform Cue	-	-	The platform cue used was created using a small metal stand and white spherical foam ball. These can likely be purchased at any store with home improvement materials (i.e. Walmart, Rona etc.)
Mainstays 71" Floor Lamp	Walmart	HW-F0377SLV
ANY-Maze Behavioural Tracking Software	Stoelting Co.	60000	There are ANY-maze® bundles that include the camera with or without a computer and accessories.
Compact Video Camera	Logitech	V-U0023
Laptop	Hewlett-Packard	HP Pavilion dv6 Notebook PC	Laptop Specifics: AMD A6-3420M APU with Radeon HD Graphics 1.50 GHz, 6.00 GB RAM, 64-bit operating system.
Americana Non-toxic Acrylic Paint	DecoArt	DAO67-9	This can be ordered on the DecoArt site or purchased in store at DecoArt retailers.
Poster Board	Walmart	PA-1961