Psychopharmacology 3

Question 1

Give some statistics for alzhiemers

Answer 1

Risk increases with age
4th leading cause of death
F = M

Question 2

How does the brain age during AD

Answer 2

Brain ageing
Preclinical AD - similar to normal ageing
Mild cognitive impairment
Moderate AD
Severe AD

Question 3

Where is the first signs of AD seen

Answer 3

Entorhinal cortex then hippocampus.
Affected areas begin to shrink then nerve cells die.
Next - enlarged ventricles

First clinical sign - memory loss

Question 4

When are the first signs of AD seen

Answer 4

Can be 10-20 years before symptoms occur

Question 5

How does death usually occur in AD

Answer 5

Aspiration pneumonia or other infections

Question 6

How is AD diagnosed

Answer 6

Cognitive assessment - MMSE
Blood tests
MRI scan

Only definite way - postmortem

Question 7

What is seen on postmortem for AD

Answer 7

• neurofibrillary tangles
• neuritic plaques
• Early cell death in hippocampus and medial temporal lobe
• Reduction in acetylcholine levels

Question 8

What pathological models have been used for AD

Answer 8

Beta-amyloid injections
Ach antagonists
Lesions
Aluminium
Tau

Important to ensure constructive and predictive validity

Question 9

What psychological models have been used for AD

Answer 9

DMTS - delayed match to place (water maze)
Spatial learning and memory
Object recognition

Important to ensure face validity

Question 10

What is the function of acetylcholine

Answer 10

Attention
Arousal
Memory

Question 11

What two receptors do Ach bind to

Answer 11

Muscarinic and nicotinic

Question 12

What happens to Ach in AD

Answer 12

Decreased release of ACh in basal forebrain neurons

Question 13

Give some AChase inhibitors

Answer 13

Donepezil
Rivastigmine

Question 14

What is delayed match to place

Answer 14

Delay in matching the surroundings of a water maze to the platform.

Can change delays between practices to look at different memory types

Question 15

What happens to rats in DMTP when given scopolamine (anticholinergic drug)

Answer 15

Impairs long term memory

Question 16

What reverses these scopolamine effects

Answer 16

Rivastigmine

Question 17

What effect does beta amyloid and scopolamine have on each other

Answer 17

Both increased latency of water task more than just one or the other therefore this suggests that they have an additive effect on one another.
Scopolamine more effective than beta amyloid

Question 18

What is tau

Answer 18

a microtubule associated phospho-protein

Question 19

Where is tau found

Answer 19

Normally in neurons but patholoigical in glial cells

Can also be found in kidney, pancreas, muscles

Question 20

What is the function of tau normally

Answer 20

Promote tubulin assembly into microtubules
Bundling of microtubules
Tau stabilises the cytoskeleton
Neural morphology and axonal growth

Question 21

What happens to tau in AD

Answer 21

Morphology change where it tangles and accumulates in the somatodendritic neuron compartment.

Question 22

What causes tau to morphologically change

Answer 22

Tau phosphorylation is needed its development however abnormal phosphorylation of tau occurs in AD which destabilises the microtubule and causes aggregation.`

Unsure if posphorylated tau causes AD or if AD causes tau posphorylation

Question 23

How is Tau posphorylation of tau carried out in the lab

Answer 23

With okadaic acid

Question 24

How is AD and aging determined

Answer 24

AD has APP dysfunction
APP develops toxic function to produce amyloid plaques

Question 25

What role does APP have in tau in AD

Answer 25

APP intensifies tau pathology which causes its spread throughout the brain in a chain reaction

Question 26

What are the 10 stages of tau spread in AD

Answer 26

Trans-entorhinal cortex
Entorhinal cortex
Hippocampus
Temporal pole
Inferior temporal cortex
Mid-temporal cortex
Polymodal association areas
Secondary sensory or motor cortex
Primary sensory and motor cortex
All neocortical areas and many subcortical nuclei

Question 27

What did Knox et al 2015 show regarding AD

Answer 27

Tau can be introduced into hippocampal neurons for vivo and in vitro studies using Polymeric alkylpyridinium salts (PAPs)
Exogenous tau does not cause major distruption but phosphorylation causes congitive deficit and reduced LTP

Those with Tau, PAPs and okadaic acid were significantly longer in swim studies.

Histology - PAPs (showed no tau), PAPs and tau (delivered tau well into neurons), triple (extends into distal dendrites)

Therefore - confirmed that hyperphosphorylation of tau is crucial for neuronal malfunction

Question 28

Give some future therapeutic targets for AD

Answer 28

Prevention of protein aggregation or fibre dissolution

Question 29

How did the frontotemporal dementia modelled PLB2Tau rat become needed

WIDER READING - Koss et al 2016

Answer 29

Previously existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments.

Question 30

How did the PLB2Tau rat present

WIDER READING - Koss et al 2016

Answer 30

demonstrated early emerging (~6months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a home cage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12months of age in the corner learning but not in the water maze task.

Question 31

How did APPswe/PS1dE9 double transgenic mice preform in the Barnes maze

WIDER READING - O’Leary et al 2009

Answer 31

Impaired learning (determined by latency, distanced traveled, errors and hole deviation errors) whilst less likely to use spatial search strategy to find the escape hole in the barnes maze compared to wild type mice.

Shows this mice type have impaired visuo-spatial learning and memory at 16 months of age.

Question 32

What was shown regarding anaesthesia and AD mice

WIDER READING - Perucho et al 2010

Answer 32

Possible AD risk using anaesthesia -
Anaethetised the mice twice a week for 3 months with isoflurane. Showed - ong lasting reduced exploratory behavior, increased Aβ aggregates and high molecular weight peptides.

This was not present in WT mice.just alzheimer model mice (AβPPswe mice)

Question 33

What was shown regarding Okadaic acid and NDMA antagonists in mice

WIDER READING - Kamat et al 2013

Answer 33

Treatment with NMDA antagonist, MK801 (0.05 mg/kg, i.p.) for 13 days significantly prevented OKA-induced changes I.E - increased mRNA and protein expression of Tau, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Calpain and GSK3β in the hippocampus and cerebral cortex.

These results infer that NMDA antagonist MK801 and memantine are effective against OKA-induced neurotoxicity. Therefore, the present study clearly indicates the involvement of NMDA receptor in OKA (ICV)-induced Tau hyperphosphorylation.

Question 34

What was found regarding a GluK2 KO and autism

WIDER READING - Micheau et al 2014

Answer 34

GLUK2 KO showed
- Anxiety was recorded in the elevated plus maze, social behavior in a three-chamber apparatus, and cognition in different water maze protocols. Deletion of the GluK2 gene reduced locomotor activity and sociability as indicated by the social interaction task.
GluK2 KO mice learnt to locate a hidden platform in a water maze surrounded by a curtain with hanging cues faster than wild-type mice. They maintained a bias toward the target quadrant when some of these cues were removed, at which point wild-types orthogonalized the behavior and showed no memory.

Shows that - glutamatergic dysfunction underlying a number of social- and cognition-related phenotypes relevant to ASD.