Depression and Alziehmers

Question 1

List 5 symptoms of depression

Answer 1

Loss of pleasure/interest
Depressed mood
Fatigue
Decreased concentration
Insomnia or hypersomnia

Question 2

Discuss the pathophysiology of depression
Monoamine hypothesis

Answer 2

The monoamine hypothesis states that depression is caused by a functional deficiency in monoamine neurotransmission (noradrenaline, serotonin, depression)

However, Various factors are likely contributing to depressive symptoms in a multifactorial manner.

The monoamine hypothesis is insufficient as an explanation for depression.

Question 3

What is depression suggested to be associated with?

Answer 3

Neuro-degeneration and reduced neurogenesis in the hippocampus and pre-frontal cortex
(hippocampus is responsible for memory and prefrontal cortex responsible for executive tasks)

Question 4

What are psychedelics?

Answer 4

A class of psychoactive substances that can alter perception and mood and affect numerous cognitive processes.

Question 5

What are the two main sub-types of psychedelics?

Answer 5

Dopaminergic-like psychedelics; linked with energetic and empathogenic like effects (DOPAMINE-LIKE)

Serotonergic-like psychedelics; linked with hallucinogenic and disorienting like effects (SEROTONIN-LIKE)

Question 6

How do psychedelics mediate their response?

Answer 6

Mediate their effects by binding to endogenous neurotransmitter receptors (Serotonin, dopamine receptors)

Psychedelics can act as partial or full agonists at multiple receptor sub-types at pre and post synaptic locations.

Psilocybin’s psychedelic and anti-depressant effects are a result of 5HT2a receptor agonism > leads to down regulation of 5HT2a receptors

Question 7

What is Psilocybin?

Answer 7

A naturally occurring substance with psychoactive properties within magic mushrooms.

Shares structural similarities with serotonin

Question 8

What form is psilocybin?

Answer 8

Psilocybin is a prodrug > converted into Psilocin (pharmacologically active) within the body

Question 9

What causes psilocybins psychedelic effects?

Answer 9

Psilocybin’s psychedelic and anti-depressant effects are a result of 5HT2a receptor agonism > leads to down regulation of 5HT2a receptors

Answer 10

Psilocybin induces decreased activity in brain regions and networks associated with depression (including the amygdala)

Question 11

What could psilocybin potentially treat?

Answer 11

Depression

Question 12

What is PTSD, list 5 symptoms

Answer 12

Post traumatic stress disorder is characterised by distress triggered by the recall of past traumatic experiences.

Question 13

What is MDMA

Answer 13

3,4 methylendioxymethamphetamine
Is a synthetic psychoactive drug with psychostimulant and psychedelic properties

Question 14

What does MDMA share properties/structures with?

Answer 14

Monoamines (dopamine and noradrenaline)

Question 15

What has MDMA been proposed to treat?

Answer 15

PTSD

Question 16

What are the stages of MDMA moa

Answer 16

1- MDMA is competitively reuptaken into the pre-synaptic nerve terminal via the dopamine transporter (DAT), Noradrenaline transporter (NAT) and Serotonin transporter (SERT)

2- Leads to less dopamine, Noradrenaline and Serotonin being taken up into the pre-synaptic nerve terminals (as MDMA is competitively taken up in its place)

3- MDMA inhibits Vesicular monoamine transporter (VMAT1/2) - DA, NA and 5HT accumulates in the cytosol

4- MDMA activates intracellular TAAR1 receptors leading to the reversal of DAT, NET, SERT and the removal of DAT, NET and SERT from the plasma membrane

5-Increase in DA, NA and 5-HT in the synaptic cleft leads to increased DA, NA and 5HT post synaptic receptor activation

Answer 17

MDMA induces decreased activity in brain regions and networks associated with anxiety, including the amygdala & increased connectivity between amygdala - hippocampus to allow reprocessing of traumatic memories.

Question 18

Define Dementia

Answer 18

Clinical syndrome characterised by a significant decline in performance in one or more cognitive domains that interfere with activities of daily living

Dementia is an umbrella term used to describe clinical syndromes characterised by cognitive deficits.

Question 19

What is the pathophysiology of Alzheimer’s
Amyloid plaques

Answer 19

Amyloid plaques; an accumulation of abnormally folded amyloid B (AB) proteins 40 or 42 amino acid residues in length (these are by products of amyloid precursor protein (APP) metabolism)
Abeta42 is most abundant within plaques due to its higher rate of fibrillation and insolubility

Question 20

Add picture of amyloid plaque formation here

Question 21

What is tau?

Answer 21

Tau is the microtubule-associated protein involved in microtubule stabilisation
The phosphorylation of tau regulates binding in microtubules

Question 22

What is the pathophysiology of Alzheimer’s
Neurofibrillary tangles of tau

Answer 22

Hyperphosphorylation of tau results in the formation of neurofibrillary tangles
Leads to the disruption of neuronal transport > leading to neuronal degeneration

Question 23

Describe the amyloid hypothesis of Alzheimer’s

Answer 23

Proposes the accumulation and deposition of oliogmeric or fibrillar amyloid-beta peptide is the primary cause of Alzheimer’s disease

Proteolytic cleavage of APP produced Abeta42

Toxicity of the amyloid oligomers and fibrils lead to the cascade of tau hyperphosphorylation

Tau hyperphosphorylation = formation of neurofibrillary tangles. leading to neuronal cell death

Occurs in the hippocampus first the becomes more widespread.

Question 24

What are the current treatments for Alzheimer’s

Give the MOA

Answer 24

In patients with mild-to-moderate
Alzheimer’s disease, the
acetylcholinesterase (AChE) inhibitors;
donepezil

AChE inhibitors prevent the breakdown of ACh
by the enzyme acetylcholinesterase (AChE)
* AChE inhibitors therefore increase ACh levels and can thus alleviate cognitive symptoms in
Alzheimer’s disease patients

In patients with moderate-to-severe
Alzheimer’s disease, the NMDA receptor
antagonist; memantine

Memantine is a low-affinity NMDA receptor antagonist that blocks excessively open NMDA receptor ion
channels to reduce glutamate mediated neurotoxicity

• NMDA receptor overactivation and subsequent glutamate mediated neurotoxicity has been associated with Alzheimer’sdisease

Question 25

Anti-amyloid and anti-tau strategies

Answer 25

AChE inhibitors and NMDA receptor antagonists have benefits for patients but its clinical outcomes are limited

Question 26

Aducanumab

Answer 26

Human monoclonal antibody that selectively binds to amyloid beta fibrils and soluble oligomers and reduces amyloid burden in a dose and time dependent manner.

Question 27

Lecanemab

Answer 27

Lecanemab targets amyloid as it begins
to form amyloid fibrils

Question 28

Donanemab

Answer 28

Donanemab targets amyloids once
amyloid fibres have formed amyloid
plaques

Question 29

What are the differences between Lecanemab and Donanemab?

Answer 29

Lecanemab and donanemab are two alternate human monoclonal antibodies
that target amyloid protein – but target amyloid at different stages.