Neurobiology of Disease 7 Flashcards
How has the prevalence of autism changed since the early 1990’s? (1)
a) increased
b) stayed the same
c) decreased
a) increased
What is the estimated prevalence of autism in the USA (in children under 8 years)? (1)
a) 1 in 10,000
b) 1 in 68
c) 1 in 10
d) 1 in 5000
b) 1 in 68
Complete the sentence relating to the prevalence of autism. (3)
The prevalence of autism is thought to be …………………. higher in the ……………………. sex than in the …………………….. sex.
5-fold
male
female
For a diagnosis of autism to be made, three symptoms must be experienced in at least two core domains.
What are the core domains in which deficits are seen in ASD? (4)
- Atypical social behaviour
- Disrupted verbal and/or non-verbal communication
- Restrictive interests and/or repetitive behaviours
- Impairments in symbolic/imaginative play
For a diagnosis of ASD to be made, deficits/symptoms must have onset before what age? (1)
3 years
Give 7 specific signs of autism in young children. (7)
Give a criterion which these symptoms must meet to be classed as ‘autistic’. (1)
- Inability to relate/communicate with children or adults
- Poor speech or lack of speech
- Inappropriate laughter or crying
- Oversensitive or undersensitive to sound
- Inappropriate playing with toys
- Difficulty dealing with changes in routine
- Oversensitive or undersensitive to touch
CRITERION: must be developmentally inappropriate behaviour
Give 6 conditions/features which may be associated with autism but which are not core features/symptoms. (6)
- Heterogenous delay in spoken language
- Epilepsy
- Mental retardation
- Motor impairments
- Sleep disturbances
- Gastrointestinal disturbances
How common are speech delay and GI disturbances in autism? (1)
Feature in about 50% of people
How is head size thought to relate to autism? (1)
People with autism have been found to have ~20% larger head size
Describe how intelligence is thought to relate to autism. (3)
Most people have normal intelligence
35-50% have intellectual disability (IQ<70)
Small minority have remarkable memory/intellect
True or false? Explain your answer if appropriate. (1)
Autism is associated with mood and anxiety disorders, as well as ADHD.
True
Give three reasons/features of ASD which make a diagnosis difficult. (3)
- No common macroscopic or microscopic neuropathology
- No specific brain region or cell type is implicated
- No biomarkers, so no prediction of who will develop the condition
As well as psychiatric and psychological assessment, give two other tests which may be helpful in diagnosing autism. (2)
- eye tracking movements
- EEG
How can eye tracking movements be useful when diagnosing autism? (1)
Autistic people tend to make less eye contact
Autism spectrum disorder is a combined diagnosis, which used to be three separate diagnoses.
What are the three diagnoses which used to be used? (3)
- Autistic disorder
- Asperger’s disorder
- Pervasive developmental disorder - not otherwise specified (PDD-NOS)
Is autism usually treated using pharmacological or non-pharmacological management? (1)
Describe this management. (1)
Non-pharmacological management
Behavioural intervention
There are two FDA-approved drugs for treating autism.
What group do these two drugs belong to? (1)
Name the drugs. (2)
What are they for? (2)
Antipsychotics
Risperidone (for aggressive and repetitive behaviour)
Aripiprazole (for irritability)
What percentage of autism is inherited through a single mendelian gene mutation? (1)
3%
5% of autism cases are inherited through chromosome abnormalities and CNVs.
What is a CNV? (1)
Copy number variation - large sections of the genome are replicated or deleted
5-10% of autism cases are thought to be due to De novo single gene mutations.
What is a De novo single gene mutation? (1)
A mutation in a gene that is present in the offspring but not inherited from either parent (may occur after fertilisation).
What is the most common type (accounting for 80-85%) of autism genetics? (1)
a) De novo single gene mutations
b) Mendelian single gene
c) Chromosome abnormalities and CNVs
d) Unknown and/or multifactorial genes
d) unknown and/or multifactorial genes
What is the chance of a child with an autistic sibling developing autism? (1)
What does this suggest about the aetiology of autism? (1)
20%
Mix between genetic and environmental risk factors
Complete the sentence relating to autism. (2)
Autism is a disorder of …………………………, especially in the ………………………….
neuronal connectivity
cerebral cortex
Give two neuroanatomical differences which may be caused by genes implicated in autism. (2)
- Altered brain growth (smaller, then larger, then size becomes normal)
- Subtle differences in cerebral neuronal columns
Describe two systems-level differences which may be caused by genes implicated in autism. (2)
- Differences in prenatal neuronal migration and axon pathfinding, leading to differences in white matter tracts and functional connectivity
- Differences in postnatal dendritic development, synaptic pruning, and neurogenesis (balance of excitation/inhibition)
Describe three cellular/molecular differences which may be caused by genes implicated in autism. (3)
- Alterations in activity-dependent protein synthesis
- Differences in neuronal activity
- Differences in neuronal cell adhesion
Complete the sentence relating to the involvement of genetics in autism. (3)
In autism, >100 susceptibility genes converge on pathways affecting …………………….., ……………………….., and ……………………..
synapse formation
neuronal activity
neuronal cell adhesion
The gene alterations often seen in autism lead to changes in synaptic function and neuronal circuitry.
Give six specific cellular mechanisms/targets that the implicated genes may affect. (6)
- Synaptogenesis and synaptic plasticity
- Protein synthesis
- Chromatin remodelling and transcription
- Protein degradation
- Phospholipid homeostasis
- Cytoskeleton dynamics
Give five specific genes which are well-known to be involved in autism. (5)
- Neurexins
- Neuroligins
- DAT
- D2 receptor
- Trio gene
The trio gene is well-known to be involved in autism.
Are mutations in this gene generally inherited or de novo? (1)
Where is the protein formed from the trio gene found? (1)
de novo
Protein found in dendritic spines of glutamatergic neurones
Neuroligin genes are often implicated in autism.
Describe what the neuroligin protein is and its functions. (4)
Synaptic cell adhesion molecules
on postsynaptic neuronal membranes
which interact with glutamatergic NMDA or GABAergic receptors
to maintain synaptic functions and the excitatory/inhibitory balance
Neurexin genes are often implicated in autism.
Describe what the neurexin protein is and its functions. (2)
Components of the presynaptic neuronal membrane
intracellular domain interacts with proteins involved in exocytosis
Neurexin and neuroligin genes are implicated in autism.
Very briefly describe the joint function of neurexins and neuroligin proteins. (2)
Proteins form links across the synaptic cleft
and maintain synaptic function
Complete the sentence relating to genetics in autism. (2)
A small percentage of ASD patients present with single mutations in genes encoding the neuroligin-neurexin cell adhesion molecules, which modifies …………………………. and the …………………… balance.
Cell/synaptic adhesion
excitatory/inhibitory
R451C mice are also known as neuroligin-3 mutants. They show altered GABA signalling.
Give one functional, one histological, and one behavioural change seen in R451C mice. (3)
What neurological condition might this mouse model be used to replicate? (1)
- Increased IPSPs
- Increased number of GABAergic neurones (shown by increased VGAT)
- Reduced social interaction behaviour
May be used to replicate autism
Describe the differences which may be seen regarding D2 receptor expression in autism. (1)
How might this difference be imaged in human postmortem brain tissue? (1)
Increased D2 receptor expression in dorsal striatum
Immunohistochemistry or in situ hybridisation for D2 mRNA
Human dopamine transporter T356M has impaired function. It has been implicated in autism.
Describe the rate of uptake and the maximum uptake that would be expected with the T356M transporter compared to wild type. (2)
Slower rate of uptake
Lower maximum uptake
Human dopamine transporter T356M has impaired function. It has been implicated in autism.
Describe the exact mutation which takes place. (1)
Why is this mutation particularly devastating for the function of the protein? (1)
On which transmembrane domain of the DAT protein does the mutation have an effect? (1)
Threonine to methionine
The threonine residue is highly conserved across species, which suggests it must be important for protein function
Mutation affects transmembrane domain 7
Human dopamine transporter T356M has impaired function. It has been implicated in autism.
In Drosophila activity assays, what effect does this mutation, and also complete knockout of the protein have on activity? (2)
Describe the activity assay in Drosophila, and how activity would have been measured. (2)
Increased activity in both forms
Flies put in tube with infrared beam separating them from food
Measure how many times fly crosses beam to get to food
Suggest 2 mechanisms by which antipsychotics may work as an adjunctive therapy for MDD along with antidepressants. (2)
- Block D2 receptors to reduce dopaminergic neurotransmission
- Block other monoamine receptors (including 5HT receptors) to make the effects of antidepressant medication more specific
Describe an environmental risk factor for autism. (2)
Maternal/paternal age:
- In females, risk doubles from 25 to 40yrs
- Risk also increased if father is 10 or more years older than mother
Give eight possible neurobiological mechanisms which may lead to development of autism. (8)
- Mitochondrial dysfunction
- Chronic neuroinflammation
- Oxidative stress
- Dysregulation of monoaminergic neurotransmission
- Glutamate/GABAergic imbalance
- Hormonal imbalance
- Immune dysregulation
- Environmental toxins and stressors
Name two neurotransmitters which may be particularly affected in autism. (2)
- Dopamine
- Serotonin
Describe briefly how serotonin may be altered in autism. (1)
Could be increased or decreased
Elevated whole blood serotonin (hyperserotonaemia) is seen in about 25% of children with autism.
Apart from autism, give another neurological condition in which hyperserotonaemia is seen. (1)
Obsessive Compulsive Disorder
Elevated whole blood serotonin (hyperserotonaemia) is seen in about 25% of children with autism.
Suggest four mechanisms by which hyperserotonaemia may occur in autism. (4)
- Increased production by enterochromaffin cells in intestine
- Increased uptake of 5HT into platelets
- Decreased metabolic breakdown of 5HT
- Altered platelet release of 5HT
Describe the effects of tryptophan depletion on autistic symptoms. (2)
Worsened repetitive behaviour
Worsened irritability
Describe how 5HT2a receptor binding is altered in adults with Asperger’s syndrome and parents of children with autism in neuroimaging studies. (1)
Decreased 5HT2a receptor binding
Alterations in 5HT deactivation mechanisms have been associated with ASD.
Give two genes/proteins which may be altered. (2)
SERT
MAO-A
Complete the sentence relating to SERT and autism. (3)
Genetic knockout of SERT alters overall ……………………., including growth, and interneuron migration to the …………………….
These changes may be related to ……………………..
brain development
cortex
autism
True or false? Explain your answer if appropriate. (1)
Due to the altered serotonergic function in autism, SSRIs often are of therapeutic benefit and are commonly prescribed
False - SSRIs have little therapeutic benefit in ASD
Describe how the short allele for the promotor region for the SLC6A4 genes may lead to a specific autistic phenotype. (3)
Short allele leads to less transcription of SERT
So reduced SERT function
Which is associated with anxiety-related traits and altered brain structure
Name a midbrain region where the SERT transporter is highly expressed. (1)
Dorsal and median raphe neurones
The SERT Gly56Ala knock-in mouse has a mutation in the SERT protein, and may be able to model autism.
Describe the effects on:
a) blood serotonin levels
b) raphe neurone firing rate
c) behaviour
of the SERT Gly56Ala mutation. (3)
a) enhanced 5HT levels
b) reduced raphe neurone firing
c) reduced sociability (with repetitive interests)
True or false? Explain your answer if necessary. (1)
It is thought that altered gut microbiome may contribute to autism, specifically, the altered serotonergic signalling seen in autism.
True
Briefly describe how the gut bacteria Lactobacillus reuteri may be able to alter ASD phenotype via the gut-brain axis. (2)
- Upregulate plasma and brain levels of oxytocin
- Which increases social behaviour in mouse models of ASD
Briefly describe how the gut bacteria Lactobacillus rhamnosus may be able to affect ASD phenotype. (4)
- Produces GABA
- Regulates GABA receptors in the brain
- Decreased stress responsiveness
- Decreased anxiety and depression-like behaviours
Briefly describe how the gut bacteria Bifidobacterium longum may be able to affect ASD phenotype. (3)
- Upregulates BDNF
- Augments neuronal plasticity in enteric nervous system
- Reduces anxiety and depression-like behaviours in mice
Briefly describe how the gut bacteria Bacteroides fragilis affects ASD phenotype. (3)
- Improves anxiety-like behaviour
- Improves repetitive behaviour
- Improves communication
Describe the general mechanisms by which the gut microbiome may contribute to behaviour seen in autism. (4)
- Altered gut microbiome leads to altered products and immune response
- Gut and systemic immune response lead to oxidative stress, increased gut permeability, increased BBB permeability
- Neuroinflammation leads to behaviour changes
True or false? Explain your answer if appropriate. (1)
In addition to the bacteria themselves producing serotonin, gut bacteria can also alter serotonin homeostasis to affect neurotransmission.
True - for example bacteria may be involved in tryptophan metabolism and/or 5HT breakdown
Autism is often associated with ‘leaky gut’.
Describe how this may impact on gut-brain axis signalling. (4)
- Increased permeability of GI tract
- Coupled with gut dysbiosis
- So bacterial products (eg. neurotransmitters) and inflammatory cytokines can be transported to blood and brain more easily
- So gut-brain signalling may be enhanced
Stimulating the maternal immune system may produce autism-like behavioural deficits in offspring.
Give two molecules which could be used to stimulate the maternal immune system. (2)
- LPS (lipopolysaccharide)
- Poly I:C
Stimulating the maternal immune system may produce autism-like behavioural deficits in offspring.
Give two changes seen in the brain, and three behavioural changes which may be observed in offspring. (5)
- Abnormal brain cell development (eg. purkinje cells, neurones, microglia)
- Brain damage
- Spatial memory deficits
- Aberrant social behaviours
- Anxiety-like behaviours
Stimulating the maternal immune system may produce autism-like behavioural deficits in offspring.
Describe what you would expect the effects to be of treatment with Bacteroides fragilis in the offspring, in terms of the open field test? (1)
Bacteroides corrects the reduced time and entries into the centre, that is seen in maternal immune activation offspring.
Describe the HPA axis. (4)
Hypothalamus paraventricular nucleus releases corticotrophin-releasing hormone (CRH)
Anterior pituitary releases adrenocorticotrophic hormone (ACTH)
Adrenal glands (cortex) release cortisol
Cortisol causes negative feedback
Name the principal endogenous glucocorticoid hormone in the following species. (2)
a) human
b) rodents
a) cortisol
b) corticosterone
Which of these is the most accurate size of CRH and ACTH? (1)
a) 200aa sequence
b) 4aa sequence
c) 40aa sequence
d) 1000aa sequence
c) 40aa sequence
CRH = 41 amino acids
ACTH = 39 amino acids
Briefly describe the synthesis of CRH and ACTH. (2)
Prepro-peptides are produced
These are cleaved to form CRH/ACTH
Does ACTH or cortisol have a longer half life? (1)
Cortisol
Describe the approximate half lives of human ACTH and cortisol. (2)
ACTH = 19 minutes
cortisol = 49 minutes
Where are the adrenal glands located, and what is their function? (2)
Located above kidneys
Produce corticosteroids mineralocorticoids, and catecholamines
Name the two general regions of the adrenal glands. (2)
What is the function of each of these regions? (2)
Cortex - produces steroid hormones
Medulla - produces catecholamines
Name the three zones of the adrenal cortex. (3)
Zona glomerulosa
Zona fasciculata
Zona reticularis
Name the cells in the adrenal medulla which produce catecholamines. (1)
Chromaffin cells
Name two specific steroid hormones which are produced by the adrenal cortex. (2)
Cortisol
Aldosterone
As well as the HPA axis, describe how the sympathetic nervous system may influence activity of the adrenal gland. (3)
- Sympathetic neurones extend from intermediolateral horn (IML) of spinal cord to adrenal gland
- Specifically, SNS innervates adrenal medulla
- And stimulates release of catecholamines into the blood
True or false? Explain your answer if applicable. (1)
Endocrine control of the adrenal gland is responsible for producing the stress response.
True and false:
- Endocrine control produces the stress response via cortisol
- But autonomic control also contributes via catecholamines
Describe how stress causes the stress response via the HPA axis and autonomic nervous systems. (3)
- Stress activates paraventricular nucleus in hypothalamus and sympathetic nervous system (intermediolateral horns of spinal cord)
- Increased stimulation of adrenal glands
- Increased cortisol and catecholamines released
Name the central pacemaker which normally controls the circadian rhythm of cortisol release. (1)
What factor ‘sets’ this pacemaker? (1)
Suprachiasmatic nucleus (SCN)
Light information from the retina sets the pacemaker.
Briefly describe the two systems which are thought to control the circadian rhythm of the adrenal gland. (2)
- SCN controlling the HPA axis (eg. ACTH)
- Peripheral adrenal clock regulating cholesterol action and sensitivity to ACTH
Briefly describe how the central pacemaker (SCN) is able to contribute to the circadian rhythmicity of the adrenal gland. (2)
SCN activates paraventricular nucleus of hypothalamus in a circadian fashion
So CRH and then ACTH is released according to the pattern set by the SCN
Describe the mechanism of how the peripheral adrenal clock contributes to the circadian rhythmicity of cortisol production. (3)
CLOCK and BMAL1 gene expression regulated in circadian rhythm (via input from SCN)
CLOCK and BMAL1 together induce transcription of StAR gene
StAR gene regulates production of cortisol, and as it is produced in a circadian rhythm, cortisol is produced in a circadian pattern
Name three genes in the adrenal gland which help to control the circadian production of cortisol. (3)
CLOCK
BMAL1
StAR
Give two specific functions of the StAR gene in the adrenal gland which help to regulate the production of cortisol in a circadian manner. (2)
- Regulates cholesterol migration in cell (cholesterol required for cortisol synthesis)
- Regulates adrenal sensitivity to ACTH
In humans, at what time of the day do cortisol levels reach their peak? (1)
What time do they reach their trough? (1)
Why are they thought to reach peak at this particular time? (1)
Peak at 08:00
Trough in early morning - about 02:00 to 04:00
Thought to reach peak at 08:00 ready for metabolic demand of the day - peak precedes/predicts energy demand
In rodents, at roughly what time of the day do corticosterone levels reach their peak? (1)
Why is this different to humans? (1)
Peak reached at about 12:00 or early afternoon
Rodents active at night rather than in the day
What would be the effect on the circadian peak of corticosterone, if the clock gene was mutated in mice? (1)
How would this change in corticosterone peak be related to daily activity levels? (1)
Delay in corticosterone peak
Peak is now a response to activity instead of preparing for activity
In addition to the circadian pattern of corticosteroid release in humans and rodents, there is a frequent bursting pattern (a pulsatile pattern) on top of the diurnal rhythm.
What is the name of this episodic bursting which occurs throughout the day? (1)
Ultradian rhythm
Fill in the gaps, related to corticosteroids and the circadian rhythm. (2)
The stress response is able to ……………………… the normal circadian rhythm and cause ………………………….. in cortisol.
override
huge bursts
Give two neurobiological processes which are regulated by normal, basal corticosterone levels. (2)
Glutamate transmission
Hippocampal LTP
Give three types of stress that can stimulate the HPA axis. (3)
- Physical
- Psychological
- Metabolic
Give four effects of catecholamines in the fear-fight-flight response. (5)
- Increased heart rate
- Increased blood pressure
- Bronchodilation
- Increased respiration
- Increased blood flow to skeletal muscle
Give six effects of cortisol in response to stress. (6)
- Increased energy metabolism
- Increased lipolysis and proteolysis
- Gluconeogenesis
- Reduced immune response and inflammation
- Reduced gut function
- Reduced reproductive functions
Describe how reduced gut function, immune function, and reproductive function may aid the fight/flight response. (3)
Conservation of energy
Give four short-term behavioural/cognitive changes which occur in response to activation of the HPA axis. (4)
- Increased anxiogenic behaviours
- Increased arousal
- Increased scanning attention
- Increased memory
Give 11 maladaptive changes which may occur due to chronic stress and chronic activation of the HPA axis and adrenal glands. (11)
- Depression and anxiety
- Sleep disturbances
- Attentional disruption
- Memory less (neurodegeneration)
- Altered cognition
- Cardiovascular disease (including increased CV tone)
- Hyperglycaemia, insulin resistance, diabetes
- Functional bowel syndrome
- Susceptibility to infection
- Altered reproductive function (sexual disorders, premature labour)
- Reduced growth
Which of the following interventions has been shown to increase plasma ACTH and/or corticosterone in rodents?
a) tub lacking bedding
b) increased food availability
c) footshock
d) forced swim
e) circular arena
f) elevated pedestal
g) restraint
All except b) increased food availability
Name the two types of receptor for adrenal steroid hormones. (2)
- Mineralocorticoid receptors
- Glucocorticoid receptors
Describe the affinities of the mineralocorticoid and glucocorticoid receptors for cortisol. (2)
Link the affinities to what circulating levels of cortisol they may be activated by.
Mineralocorticoid = high affinity (so occupied by low basal circulating levels of cortisol)
Glucocorticoid = low affinity (so occupied by circadian/stress high levels of cortisol)
Describe where in the cell the mineralocorticoid and glucocorticoid receptors are typically found. (2)
mineralocorticoid = predominantly cytosolic
glucocorticoid = membrane bound or cytosolic
Describe the general action of activated cytosolic mineralocorticoid and glucocorticoid receptors. (1)
Act in the nucleus to alter gene expression of certain proteins
Briefly describe the two types of glucocorticoid receptor that are located on the cell membrane. (2)
- Classical receptors (same as those found in cytoplasm)
- GPCR which responds to glucocorticoids
Describe the general action of activated membrane-bound glucocorticoid receptors. (1)
Alteration in cellular signalling
Compare the distribution of glucocorticoid and mineralocorticoid receptors in the brain. (2)
Glucocorticoid receptors widespread
Mineralocorticoid receptors mainly in limbic areas
Give four brain regions where mineralocorticoid receptors are particularly prevalent. (4)
- Lateral septum
- Hippocampus
- Hypothalamus
- Locus coeruleus (brain stem)
What is the role of the hypothalamic corticosteroid receptors thought to be? (1)
Act as part of the negative feedback loop of the HPA axis
What is the role of the corticosteroid receptors in the locus coeruleus thought to be? (1)
Direct part of the stress response - release of noradrenaline
Name the brain region that is thought to be the link between stress and Alzheimer’s disease. (1)
Locus coeruleus
The locus coeruleus is responsible for what neurotransmitter? (1)
Noradrenaline
Where is the locus coeruleus located in the brain? (1)
Brain stem
The locus coeruleus send out noradrenergic projections to which parts of the brain? (1)
The whole cerebral cortex
Give an amino acid, and a neurotransmitter which are precursors for noradrenaline. (2)
Tyrosine
Dopamine
A way of measuring neuronal activity is to stain for C-Fos.
What is C-Fos, and how can it indicate neuronal activity? (2)
Immediate early response gene
It is expressed in response to neuronal activity (increased staining means increased neuronal activity).
Stress can be induced in rats by putting them in a chamber with added predator odour.
Describe and explain the signal you would expect to be given off from C-Fos staining in the locus coeruleus in this situation. (2)
Increased signal
Because more C-Fos produced due to more activity in locus coeruleus (due to activation of HPA axis and corticosteroids activating LC)
Stress can be induced in rats by putting them in a chamber with added predator odour.
Describe what you would expect to see with regards to the following neuronal properties in the locus coeruleus in this situation. (3)
a) spontaneous discharges
b) input resistance
c) Excitability
For b) and c), describe how this would be shown in experimental conditions. (2)
Give a sentence explaining what this means with regards to the relationship between stress and the locus coeruleus. (1)
a) increased spontaneous discharge rate
b) increased input resistance (shown as a larger depolarisation in response to a current)
c) increased excitability (shown as higher discharge rate in response to a current injection)
This means that stress activates the locus coeruleus.
Stress can be induced in rats by putting them in a chamber with added predator odour.
Describe four behaviours you would expect to see on an open arm maze in this situation. (4)
Give a sentence to describe the relationship between stress and behaviour. (1)
- Reduced open arm entries
- Reduced open arm time
- Increased freezing time
- Reduced closed arm distance
This shows that stress causes an increase in anxious behaviour.
Name the brain region which may mediate an increase in anxious behaviour in response to stress. (1)
Locus coeruleus
Describe how the locus coeruleus is altered in Alzheimer’s disease. (1)
It degenerates
Describe a hypothesis which relates to stress, the locus coeruleus, and Alzheimer’s disease. (2)
Increased or chronic stress causes excitotoxicity of LC neurones (as LC is activated in stress response).
LC then degenerates and contributes to Alzheimer’s disease.
True or false? Explain your answer if necessary. (1)
It is thought that the locus coeruleus only contributes to Alzheimer’s disease when it starts to degenerate.
False - Stress and overactivation of the LC may contribute to the early stages of AD (before LC starts to degenerate)
Name the main neurotransmitter thought to be involved in the early stages of stress and AD, when the locus coeruleus is overactive. (1)
To much noradrenaline
Briefly describe three mechanisms which may allow stress and overactivation of the locus coeruleus to contribute to early Alzheimer’s disease pathology. (3)
- APP internalised from cellular membrane to endosomes following prolonged adrenergic synaptic activity
- b2 receptor activation by NA increases y-secretase catalytic activity
- Activation of adrenergic receptors induces expression of BACE1 (beta secretase)
One of the mechanisms by which overactivation of the locus coeruleus by stress may contribute to early Alzheimer’s pathology is the following:
APP internalised from cellular membrane to endosomes following prolonged adrenergic synaptic activity
Describe how this would contribute to Alzheimer’s pathology. (2)
When APP is in the endosome, it can act as a substrate for b and y secretases
This pathway produces amyloid plaques
One of the mechanisms by which overactivation of the locus coeruleus by stress may contribute to early Alzheimer’s pathology is the following:
b2 receptor activation by NA increases y-secretase catalytic activity
Describe how this would occur. (2)
b2 receptor activation interacts with b-arrestin 2 protein
b-arrestin 2 protein directly interacts with a-1A subunit of y-secretase
One of the mechanisms by which overactivation of the locus coeruleus by stress may contribute to early Alzheimer’s pathology is the following:
Activation of adrenergic receptors induces expression of BACE1 (beta secretase)
Describe how this would contribute to Alzheimer’s pathology. (1)
beta secretase enhances amyloidogenic processing pathway of APP
Give two possible ways in which locus coeruleus degeneration may lead to Alzheimer’s (and potentially Parkinson’s) disease. (2)
- LC degeneration leads to neuroinflammation
- Reduced NA transmission (contributes to cognitive dysfunction)
As well as physical neuronal degeneration in the locus coeruleus leading to neuroinflammation, give two other mechanisms by which neuroinflammation may be caused by LC degeneration. (2)
Microglia have adrenergic receptors so can be influenced by changes in NA activity (seen when LC degenerates).
Loss of NA may also lead to BBB disruption.
Complete the sentence relating to corticosteroids and the brain. (2)
The level of corticosteroids in the body should be in its optimal range - too low causes ………………………., and too high causes ……………………..
Addison’s disease
Neurodegeneration
Give five beneficial effects of chlorpromazine in schizophrenia treatment. (5)
- Reduced apathy
- Increased interaction with the environment
- Reduced emotion
- Reduced aggression
- Improved positive symptoms of schizophrenia
