Animal Models of Alzheimer's Disease

Question 1

Give some anatomical differences found in alzhiemer’s brains

Answer 1

Large lateral ventricles
Reduced cortex - atrophy
Wider gyri
Temporal lobe atrophy
Basal ganglia atrophy
Hippocampus atrophy

Question 2

What areas of the brain are atrophied first in Alzheimer’s (in order)

Answer 2

Hippocampus (poor short term memory)
Temporal memory (poor word finding)

Question 3

What are the two main types of alzheimer’s disease

Answer 3

Sporadic (99%)
Familial (1%)

Question 4

What genes are associated with familial Alzheimer’s disease

Answer 4

APP gene
PS1
PS2

Question 5

What 4 processes occur in Alzheimer’s disease

Answer 5

Brain degeneration
Inflammation
Proteinopathy - amyloid plaques
Decreased glucose metabolism

Question 6

Causes of alzheimer’s

Answer 6

Genes
AGE - biggest
Lifestyle

Question 7

What are the two main histological hallmarks of AD

Answer 7

Amyloid - senile plaques
TAU - neurofibrillary tangles

Question 8

Describe the amyloid and tau pathways

Answer 8

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.

Question 9

How is the alpha and tau pathways changed in AD

Answer 9

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.

Question 10

Do all amyloid plaques cause cognitive decline

Answer 10

No - only 2-mer and 12-mer amyloid plaques are

Question 11

Give some key features of viral gene delivery systems

Answer 11

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.

Question 12

How are viruses used in AD studies

Answer 12

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.

Question 13

Through immunochemistry, what happens to amyloid over time once infected with AD susceptible genes via adenoviruses

Stoppelkamp 2011

Answer 13

Amyloid becomes withdrawn and less dense

Question 14

Through immunochemistry, what happens to tau over time once infected with AD susceptible genes via adenoviruses

Stoppelkamp 2011

Answer 14

Becomes more disorganised and clustered - initiating apoptosis

Question 15

Why are transgenic mice preferred for AD studies

Answer 15

Can help determine how the proteins are produced
Which protein species are harmful
The cellular mechanisms that cause degeneration

Question 16

What substance is considered neuroprotective for AD

Stoppelkamp 2011

Answer 16

Caffeine

Question 17

Why is transgenic mice difficult to study in AD

Answer 17

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

Question 18

How were transgenic mice modified to convey AD in vivo (PLB mice)

Answer 18

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)

Question 19

What is the PLB4 mouse

Answer 19

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.

Question 20

What is the link found in PLB4 mice between DM and AD

Answer 20

Obesity –> insulin resistance in the brain and other tissues –> BACE1 is activated –> amyloid pathology and tau pathology occurs.

Question 21

How does diabetes cause insulin resistance in the brain

EXTRA READING - Lee 2018

Answer 21

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

Question 22

How does high glucose result in amyloid beta plaque production

EXTRA READING - Lee 2018

Answer 22

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

Question 23

What can be used to treat diabetes-induced dementia

EXTRA READING - Lee 2018

Answer 23

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

Question 24

How does resveratrol help prevent diabetes-induced dementia

EXTRA READING - Lee 2018

Answer 24

stimulating amyloid beta clearance and protecting the integrity of blood-brain barrier and neuronal structure and increase ACh activity in STZ-injected diabetic rats

Question 25

What did the BACE knock-in show regarding mice behaviour

EXTRA READING - Plucinska 2014

Answer 25

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

Question 26

Through immunochemistry, what happens to tau over time once infected with AD susceptible genes via adenoviruses

Stoppelkamp 2011

Answer 26

Becomes more disorganised and clustered - initiating apoptosis