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Questions and Answers
Which enzyme is responsible for starting the process that leads to pathological amyloid plaque formation?
Low levels of acetylcholine (ACh) in Alzheimer's disease are mainly due to inadequate production of ACh.
False
What neurotransmitter is found in high levels and can cause cytotoxic effects in Alzheimer's disease due to over-activation of NMDA receptors?
Glutamate
In Alzheimer's disease, the drug __________ is used to inhibit acetylcholinesterase to increase the availability of ACh.
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What is one of the challenges in treating Alzheimer's disease with current pharmacological approaches?
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The only focus of recent clinical trials for Alzheimer's disease has been on symptom management.
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What reaction might the aggregation of β-amyloid in Alzheimer's disease cause?
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Excessive __________ in synapses is a result of dysfunction in reuptake proteins which could be caused by β-amyloid.
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Match the drug to its mechanism of action:
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Alzheimer’s disease is characterized by the presence of pathological aggregations, atypical inflammation, and neurotransmitter abnormalities.
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What are the two pathological features commonly associated with Alzheimer's disease?
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Aβ42 is considered the non-pathogenic subtype of amyloid-beta formed in Alzheimer's disease.
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What is the role of tau proteins in the context of Alzheimer's disease?
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The cleavage of the amyloid precursor protein (APP) by _____ secretase leads to the formation of Aβ.
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Match the following treatments to their intended effect in Alzheimer's disease:
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Which drug was approved in June 2021 for patients with mild cognitive impairment or mild dementia but faced controversy over its efficacy?
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Neurotoxic effects of amyloid plaques facilitate neuronal communication.
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What is the significance of the APOE4 gene in Alzheimer's disease?
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_____ cut by (alpha) α-secretase leads to normal APP processing without plaque formation.
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What percentage of phase 3 clinical trials in 2024 focuses on disease modifying therapies (DMT) for Alzheimer's disease?
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Which of the following is a common effect of opioids?
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Cannabis primarily exerts its effects via CB2 receptors.
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What neurotransmitter's release is inhibited by morphine in the ventral tegmental area (VTA)?
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The drug known as MDMA is commonly referred to as ____.
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Match the following drugs with their primary effects:
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Which neurotransmitter is primarily associated with the euphoric effects of psychostimulants?
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Opioids act as agonists primarily on sigma receptors.
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Name one endogenous lipid that acts as an agonist at cannabinoid receptors.
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Cognitive control of emotions is enhanced by decreased activity in the ______.
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Which two stimulants are known to increase dopamine, serotonin, and norepinephrine levels?
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What hormone is released from the stomach to stimulate hunger?
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Alcohol decreases the release of glutamate in the brain.
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Which neurotransmitter does alcohol increase by inhibiting GABA neurons?
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Alcohol enhances actions on GABA A receptors, resulting in increased ______.
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Match the following effects of alcohol with their corresponding mechanisms:
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Which of these describes the action of β-endorphins in relation to GABA?
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Alcohol is considered a stimulant because it increases neural activity.
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What is one consequence of alcohol interfering with neuronal lipid membranes?
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Alcohol acts as a positive allosteric modulator of ______ receptors.
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Which of the following substances has a strong association with decreasing aversive activity in the amygdala?
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Study Notes
Alzheimer's Disease: Brain Changes
- Characterized by significant brain shrinkage (cellular loss)
- Large numbers of neurons cease functioning
- Neuronal connections are disrupted, hindering communication, and leading to neuron death
- Memory areas like the entorhinal cortex and hippocampus are initially affected.
- Progresses to the cerebral cortex, impacting language, reasoning, and social behavior
- Damage becomes widespread throughout the brain
- Individuals gradually lose the ability to live and function independently
Alzheimer's Disease: Prevalence and Pathology
- Most common type of dementia
- Affects 10% of the population over 65
- 50% of those older than 85 are affected
- Two key pathological features:
- Formation of β-amyloid (Aβ) plaques
- Neurofibrillary tangles due to hyperphosphorylation of the tau protein
Alzheimer's Disease: Treatment Focus and Clinical Trials
- Currently, treatments mainly focus on managing symptoms, offering minor improvements in cognitive function or delaying cognitive decline
- No available medication can stop or reverse the underlying progression of the disease.
- Disease-modifying therapies (DMTs) account for the majority (65%) of Phase 3 clinical trials
- 32 potential drugs are currently in Phase 3 clinical trials, with an additional 81 in Phase 2
Alzheimer's Disease: Pathogenesis of β-Amyloid (Aβ)
- Aβ is a fragment of a larger protein known as β-amyloid precursor protein (APP)
- APP is located in the neuronal membrane and plays a role in regulating synapse formation
- APP undergoes cleavage by different enzymes:
- α-secretase (dominant pathway) produces sAPPα peptide, preventing plaque formation
- β-secretase produces sAPPβ peptide, initiating the formation of Aβ
- γ-secretase cleaves the remaining protein, resulting in Aβ formation. The position of this cut determines if pathogenic or not.
Alzheimer's Disease: Pathogenic Role of Aβ
- Aβ42, a long form of Aβ, is considered the pathogenic subtype
- Aβ oligomers—collections of Aβ42 fragments—form prior to plaque formation
- Some oligomers misfold, acting as prions, causing other oligomers to misfold and facilitate plaque formation.
- These aggregates damage neuronal membranes, leading to synaptic loss and neuron death
- They also interfere with communication between neurons by disrupting ion channels, ion flow, receptors and synaptic communication.
Failed Approaches for Pharmacological Treatment of Alzheimer's Disease
- Modulating enzymes involved in Aβ production has been unsuccessful:
- Semagacestat, an inhibitor of γ-secretase, failed trials
- Tarenflurbil, which shifts the cleavage site, also failed trials
- β-secretase (BACE1) inhibitors like Verubecestat, Atabecestat, and Lanabecestat were unsuccessful, potentially even worsening cognitive function.
Strategies for Pharmacological Treatment targeting Aβ:
- Preventing Aβ42 aggregation:
- Bind to Aβ42 to prevent its aggregation and plaque formation (e.g., Tramiprosate, failed in Phase 3)
- Removing Aβ oligomers:
- Prevent plaque formation
- Upregulate Aβ transport proteins (P-glycoprotein, LRP1) to remove Aβ from the brain
- Immunization for Aβ42:
- Uses the immune system to target and remove Aβ42 or amyloid plaques
Controversy Surrounding Aduhelm (an Antibody Targeting Amyloid Plaques)
- Approved in June 2021 for patients with mild cognitive impairment or mild dementia stage of disease
- Binds to aggregated forms of amyloid plaques, believed to facilitate clearance or digestion by glial cells
- Controversy:
- Did not demonstrate efficacy above the placebo group
- Approved based on plaque reduction despite unclear clinical improvement
- FDA advisors voted against approval with a 10-1 majority
- Several FDA advisors resigned following the approval
- MRI abnormalities, including swelling and brain bleeding, were observed in 41% of patients
Leqembi (Lecanemab) and Kisunla (Donanemab) - New Antibody Treatments for Alzheimer's Disease
- Leqembi (Lecanemab) was approved in May 2022 for patients with mild cognitive impairment or mild dementia stage of disease. It interferes with the formation of Aβ fibrils
- Kisunla (Donanemab) was approved in July 2024, utilizing a similar mechanism to Aduhelm but potentially clearing more plaques
- Early intervention is critical for these treatments
- Patients may discontinue the drugs once plaques are cleared and reintroduce them upon appearance of new plaques
- Significant side effects, including swelling and brain bleeding, continue to be a concern
Alzheimer's Disease: Apolipoprotein E (ApoE) and Tau
- Apolipoprotein E (ApoE):
- Produced by microglia
- Most prominent genetic risk factor identified for Alzheimer's Disease, particularly the ApoE4 gene
- Stabilizes Aβ aggregations
- Impairs Aβ degradation
- Enhances the activity of γ-secretase
- Potential therapeutic targets:
- Neutralization with antibodies
- Degradation or transport out of the brain
- Tau proteins:
- Stabilize microtubules aiding tubulin assembly
- Hyperphosphorylation in AD disrupts normal function
- Without Tau, microtubules cannot be properly stabilized, disrupting transport function (synaptic vesicles)
- Neurofibrillary tangles form inside neurons, causing neuronal dysfunction and death.
Approaches for Pharmacological Treatment Targeting Tau:
- Several drugs are in development with the aim of preventing tau aggregation or phosphorylation
- Preclinical studies focus on kinase inhibitors to prevent phosphorylation
"Ya, I Know That" Quiz: What starts the process leading to pathological amyloid plaque formation?
- Answer: β-Secretase
Alzheimer's Disease: Neurotransmitter Dysregulation
- Acetylcholine (ACh):
- Crucial for learning and memory
- One of the first systems affected in Alzheimer's disease
- Low ACh levels are observed due to excessive degradation by acetylcholinesterase (AChE), leading to impaired memory.
- Glutamate:
- Excessive glutamate levels in synapses occur due to dysfunction of reuptake proteins and degradation enzymes. This is often attributed to β-amyloid.
- Excessive glutamate causes over-activation of NMDA receptors, increasing calcium influx. Excess calcium is toxic and damaging to neurons.
Approaches for Pharmacological Treatment Targeting Neurotransmitters:
- Fix neurotransmitter imbalances:
- Inhibiting AChE (donepezil, galantamine) to increase ACh levels (limited efficacy, only temporary improvement)
- Block NMDA channels to limit calcium influx (memantine) (minor effects on symptoms, does not address the disease)
Alzheimer's Disease: Key Takeaways
- A chronic, progressive disease, resulting from neuronal dysfunction, death, pathological aggregations (Aβ plaques and tau tangles), inflammation, neurotransmitter abnormalities and other age-related ailments
- Ongoing research targets disease modification, with recent focus on treatment of symptoms
- Limited success of disease-modifying therapies has spurred further investigation
- Early intervention remains crucial to benefit from available therapies
- Research is actively seeking to understand if patients are treated too late in the disease progression.
Drugs of Abuse
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Opioids
- Types: Morphine (heroin), Methadone, Fentanyl
-
Mechanisms of action
- Binding to opioid receptors (mu, delta, kappa)
- G-protein coupled receptors, primarily inhibitory
- Stimulate dopamine release in the nucleus accumbens (NAc) by reducing GABA release in the VTA
- Effects: Analgesia, euphoria, respiratory depression, drowsiness, decreased appetite, addiction, and tolerance
Psychomotor Stimulants
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Cocaine
- Types: Cocaine hydrochloride, Crack cocaine
- Mechanisms of action: Blocks dopamine, norepinephrine, and serotonin reuptake by inhibiting their transporters, resulting in higher concentrations in the synaptic cleft
- Effects: Increases alertness, energy, euphoria, and motivation, can cause paranoia, anxiety, and cardiovascular problems
-
Amphetamine
- Types: Amphetamine, Methamphetamine, Methylphenidate (Ritalin)
- Mechanisms of action: Promotes release of dopamine, norepinephrine, and serotonin, and inhibits monoamine oxidase (MAO) activity, further increases neurotransmitter availability
- Effects: Increases alertness, focus, and energy, can induce euphoria and psychosis, can cause insomnia, paranoia, anxiety, and dependence
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Methylenedioxymethamphentamine (MDMA)
- Types: Ecstasy, Molly
- Mechanisms of action: Increases dopamine, norepinephrine, and serotonin by inhibiting their reuptake, but with a stronger effect on serotonin transporters
- Effects: Induces euphoria, empathy, and social connectedness, can cause hallucinations, hyperthermia, and cardiovascular problems
Cannabis
- Types: Marijuana (cannabis sativa), Hashish
-
Mechanisms of action: Binds to cannabinoid receptors (CB1 and CB2), primarily CB1 in the brain
- CB1 receptors are presynaptic, inhibitory, and modulate the release of various neurotransmitters (acetylcholine, serotonin, GABA, glutamate)
- Effects: Euphoria, relaxation, impaired memory, altered perception of time, and increased appetite (munchies), potential for anxiety, paranoia, and psychosis
Alcohol
- Types: Ethyl alcohol (ethanol)
-
Mechanisms of action: Binds to GABA receptors, particularly GABA-A receptors, increasing GABA-ergic activity and inhibition
- Additionally, alcohol enhances dopamine release by acting on the opioid system, it also inhibits glutamate activity and can have damaging effects on neuronal structure and function
- Effects: Relaxation, impaired coordination, impaired judgement, sedation, and loss of inhibition, potential for addiction, tolerance, and withdrawal symptoms
MDMA and the Amygdala
- MDMA (ecstasy, Molly) is the only drug in the list that directly affects the amygdala, a brain region associated with fear and aversive emotions.
- MDMA's effect on the amygdala involves decreasing its activity. This can lead to feelings of reduced fear, anxiety, and improved emotional regulation.
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