Psychopharmacology 3 Flashcards
Give some statistics for alzhiemers
Risk increases with age
4th leading cause of death
F = M
How does the brain age during AD
Brain ageing
Preclinical AD - similar to normal ageing
Mild cognitive impairment
Moderate AD
Severe AD
Where is the first signs of AD seen
Entorhinal cortex then hippocampus.
Affected areas begin to shrink then nerve cells die.
Next - enlarged ventricles
First clinical sign - memory loss
When are the first signs of AD seen
Can be 10-20 years before symptoms occur
How does death usually occur in AD
Aspiration pneumonia or other infections
How is AD diagnosed
Cognitive assessment - MMSE
Blood tests
MRI scan
Only definite way - postmortem
What is seen on postmortem for AD
- neurofibrillary tangles
- neuritic plaques
- Early cell death in hippocampus and medial temporal lobe
- Reduction in acetylcholine levels
What pathological models have been used for AD
Beta-amyloid injections
Ach antagonists
Lesions
Aluminium
Tau
Important to ensure constructive and predictive validity
What psychological models have been used for AD
DMTS - delayed match to place (water maze)
Spatial learning and memory
Object recognition
Important to ensure face validity
What is the function of acetylcholine
Attention
Arousal
Memory
What two receptors do Ach bind to
Muscarinic and nicotinic
What happens to Ach in AD
Decreased release of ACh in basal forebrain neurons
Give some AChase inhibitors
Donepezil
Rivastigmine
What is delayed match to place
Delay in matching the surroundings of a water maze to the platform.
Can change delays between practices to look at different memory types
What happens to rats in DMTP when given scopolamine (anticholinergic drug)
Impairs long term memory
What reverses these scopolamine effects
Rivastigmine
What effect does beta amyloid and scopolamine have on each other
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
What is tau
a microtubule associated phospho-protein
Where is tau found
Normally in neurons but patholoigical in glial cells
Can also be found in kidney, pancreas, muscles
What is the function of tau normally
Promote tubulin assembly into microtubules
Bundling of microtubules
Tau stabilises the cytoskeleton
Neural morphology and axonal growth
What happens to tau in AD
Morphology change where it tangles and accumulates in the somatodendritic neuron compartment.
What causes tau to morphologically change
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
How is Tau posphorylation of tau carried out in the lab
With okadaic acid
How is AD and aging determined
AD has APP dysfunction
APP develops toxic function to produce amyloid plaques
What role does APP have in tau in AD
APP intensifies tau pathology which causes its spread throughout the brain in a chain reaction
What are the 10 stages of tau spread in AD
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
What did Knox et al 2015 show regarding AD
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
Give some future therapeutic targets for AD
Prevention of protein aggregation or fibre dissolution
How did the frontotemporal dementia modelled PLB2Tau rat become needed
WIDER READING - Koss et al 2016
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.
How did the PLB2Tau rat present
WIDER READING - Koss et al 2016
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.
How did APPswe/PS1dE9 double transgenic mice preform in the Barnes maze
WIDER READING - O’Leary et al 2009
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.
What was shown regarding anaesthesia and AD mice
WIDER READING - Perucho et al 2010
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)
What was shown regarding Okadaic acid and NDMA antagonists in mice
WIDER READING - Kamat et al 2013
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.
What was found regarding a GluK2 KO and autism
WIDER READING - Micheau et al 2014
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.
