Animal Models of Alzheimer's Disease Flashcards
Give some anatomical differences found in alzhiemer’s brains
Large lateral ventricles
Reduced cortex - atrophy
Wider gyri
Temporal lobe atrophy
Basal ganglia atrophy
Hippocampus atrophy
What areas of the brain are atrophied first in Alzheimer’s (in order)
Hippocampus (poor short term memory)
Temporal memory (poor word finding)
What are the two main types of alzheimer’s disease
Sporadic (99%)
Familial (1%)
What genes are associated with familial Alzheimer’s disease
APP gene
PS1
PS2
What 4 processes occur in Alzheimer’s disease
Brain degeneration
Inflammation
Proteinopathy - amyloid plaques
Decreased glucose metabolism
Causes of alzheimer’s
Genes
AGE - biggest
Lifestyle
What are the two main histological hallmarks of AD
Amyloid - senile plaques
TAU - neurofibrillary tangles
Describe the amyloid and tau pathways
Amyloid precursor protein (APP) is cleaved by alpha and gamma-secretase (enzymes) to cleave the APP to leave a soluble APP alpha fragment. the APP-a fragment is known to increase neuron survival and plasticity.
How is the alpha and tau pathways changed in AD
The AAP is cleaved by the beta-secretase (BACE1 enzyme) instead of alpha and gamma. This causes a fragment of a different length which is called beta-amyloid which is harmful.
Beta-amyloid affects lipid oxidation, microglial activation, inflammation and apoptosis.
Tau is used to formulate the micro skeleton, in AD it is hyperphosphorylated and the microtubules are destabilised leading to apoptosis and neuronal death.
Do all amyloid plaques cause cognitive decline
No - only 2-mer and 12-mer amyloid plaques are
Give some key features of viral gene delivery systems
transfer genes into both developing and mature animals;
transduce cells with high efficiency;
be cell-type / tissue specific;
mediate high level, long-term expression;
cause limited cytotoxicity;
elicit a small/negligible immune response;
allow sufficient lengths of DNA to be introduced;
avoid over-expression;
allow regulatable expression.
How are viruses used in AD studies
Infect hosts with AD susceptible genes (amyloid, tau and BACE1) and treat them with medication to see if the symptoms of dementia can be treated.
Through immunochemistry, what happens to amyloid over time once infected with AD susceptible genes via adenoviruses
Stoppelkamp 2011
Amyloid becomes withdrawn and less dense
Through immunochemistry, what happens to tau over time once infected with AD susceptible genes via adenoviruses
Stoppelkamp 2011
Becomes more disorganised and clustered - initiating apoptosis
Why are transgenic mice preferred for AD studies
Can help determine how the proteins are produced
Which protein species are harmful
The cellular mechanisms that cause degeneration
What substance is considered neuroprotective for AD
Stoppelkamp 2011
Caffeine
Why is transgenic mice difficult to study in AD
Only look at the 1% that are genetic based AD
Varied promoters
Varied genetic backgrounds
No suitable controls
This was attempted to be fixed in the following study
How were transgenic mice modified to convey AD in vivo (PLB mice)
Knock-in - allowed to be in a specific neural locus which was tissue-specific and prevented over-expression or early expression.
Allowed for direct comparison between lines
Direct genotype to phenotype relationship
-Allowed for direct comparison between lines
Direct genotype to phenotype relationship
(Ideal to develop sensitive, early and transitional biomarker, safe, removable, single copy, stable genetics)
What is the PLB4 mouse
Transgenic mouse that expresses human BACE1 - resulted in high inflammation causing poor learning resulting in a decrease in -
Activity Spatial memory Working memory Semantic memory Anxiety
Worse with age.
What is the link found in PLB4 mice between DM and AD
Obesity –> insulin resistance in the brain and other tissues –> BACE1 is activated –> amyloid pathology and tau pathology occurs.
How does diabetes cause insulin resistance in the brain
EXTRA READING - Lee 2018
Chronic hyperglycaemia –> chronic hyperinsulinaemia –> brain insulin resistance –> impaired brain insulin signalling and limited insulin –> poor cognitve function as insulin is required especially for hippocampus function
How does high glucose result in amyloid beta plaque production
EXTRA READING - Lee 2018
Streptozotocin (STZ)-induced type 1 diabetes shows increased levels of amyloid beta as a result of inhibited APP degredation, and tau phosphorylation in hippocampus of senescence-accelerated mice
In other transgenic mouse models of AD, STZ injection-induced type 1 diabetes can aggravate amyloid beta accumulation in brain accompanied by upregulation of BACE 1 resulting in amyloid plaque formation
STZ-induced diabetic rats show atrophy of hippocampus, amyloid beta aggregation, synapse loss in brain, and impaired performance of memory and learning
What can be used to treat diabetes-induced dementia
EXTRA READING - Lee 2018
Resveratrol is a brain-permeable stilbenoid found in grapes, blueberries, raspberries, and mulberries. It is well known to exert cardio-protective, anti-cancer, anti-inflammatory, and anti-oxidative activities
How does resveratrol help prevent diabetes-induced dementia
EXTRA READING - Lee 2018
stimulating amyloid beta clearance and protecting the integrity of blood-brain barrier and neuronal structure and increase ACh activity in STZ-injected diabetic rats
What did the BACE knock-in show regarding mice behaviour
EXTRA READING - Plucinska 2014
Memory loss - social adn food preference at 3-4 months
Impaired spacial learning (Water maze) at 6 months
This was done even though mice cant get AD - showing that BACE cleavage is an underlying cause of amyloid plaques
Through immunochemistry, what happens to tau over time once infected with AD susceptible genes via adenoviruses
Stoppelkamp 2011
Becomes more disorganised and clustered - initiating apoptosis
