Alzheimer's Disease Overview and Brain Changes
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Questions and Answers

What is the enzyme that initiates the pathological process leading to amyloid plaque formation in Alzheimer's disease?

β-Secretase

How does the degradation of acetylcholine contribute to the symptoms seen in Alzheimer's disease?

Low levels of ACh result from excessive degradation by acetylcholinesterase, impairing memory.

What impact does excessive glutamate have in the synapses of individuals with Alzheimer's disease?

It causes over-activation of NMDA receptors, allowing high influx of Ca2+, which is cytotoxic and leads to neuronal death.

What are the two main pharmacological approaches mentioned for treating neurotransmitter-related issues in Alzheimer's disease?

<p>Inhibit acetylcholinesterase to increase ACh and block NMDA channels to limit Ca2+ influx.</p> Signup and view all the answers

What recent focus is highlighted regarding Alzheimer's disease treatments in current clinical trials?

<p>The major focus is on disease modification rather than just symptomatic treatment.</p> Signup and view all the answers

What question is raised about the timing of treatment initiation for Alzheimer's patients?

<p>Are the patients being treated too late?</p> Signup and view all the answers

What roles do pathological aggregations and atypical inflammation play in Alzheimer's disease?

<p>They contribute to neuronal dysfunction and death.</p> Signup and view all the answers

Why are current treatments for Alzheimer's disease considered to have minor and temporary effects?

<p>They address symptoms without modifying the underlying disease pathology.</p> Signup and view all the answers

What hormone is released from the stomach to stimulate hunger and inhibit satiety?

<p>Ghrelin</p> Signup and view all the answers

How does alcohol enhance the actions of GABA?

<p>Alcohol acts as a positive allosteric modulator of GABA A receptors, increasing inhibition in neurons.</p> Signup and view all the answers

What effect does alcohol have on glutamate release?

<p>Alcohol reduces glutamate release by increasing activity at mGluR autoreceptors and inhibiting ionotropic glutamate receptors.</p> Signup and view all the answers

What neurotransmitter's release is increased by alcohol through β-endorphin?

<p>Dopamine</p> Signup and view all the answers

In what way does alcohol interfere with neuronal structure and function?

<p>Alcohol interferes with neuronal lipid membranes and second messenger systems, causing membrane deformation and stimulating G-proteins.</p> Signup and view all the answers

What is the primary impact of ghrelin on olfactory sensitivity?

<p>Ghrelin diminishes olfactory habituation, increasing sensitivity to food smells.</p> Signup and view all the answers

What is the relationship between alcohol consumption and the amygdala's activity regarding aversive experiences?

<p>Alcohol is associated with decreasing aversive activity in the amygdala.</p> Signup and view all the answers

What mechanism allows alcohol to affect both inhibition and excitation in the brain?

<p>Alcohol enhances GABA's inhibitory effects while decreasing glutamate's excitatory effects.</p> Signup and view all the answers

What are the two primary pathological features of Alzheimer's Disease?

<p>The two primary pathological features are the formation of β–amyloid (Aβ) plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein.</p> Signup and view all the answers

In which brain areas are neurons and their connections first impacted by Alzheimer's Disease?

<p>Neurons and their connections in memory areas, specifically the entorhinal cortex and hippocampus, are impacted first.</p> Signup and view all the answers

What is the current status of treatments aimed at modifying the progression of Alzheimer's Disease?

<p>As of 2024, most treatments are focused on symptoms, with 65% of phase 3 trials investigating disease-modifying therapies.</p> Signup and view all the answers

What enzyme primarily cleaves the β-amyloid precursor protein (APP) in normal processing?

<p>The predominant enzyme that cleaves APP in normal processing is α-secretase.</p> Signup and view all the answers

Which type of Aβ is considered pathogenic and contributes to amyloid plaque formation?

<p>Aβ42, which is longer in amino acid sequence, is considered the pathogenic form leading to amyloid plaque formation.</p> Signup and view all the answers

What effects can Aβ oligomers have on neurons?

<p>Aβ oligomers can damage neuronal membranes, leading to synaptic loss, neuron death, and disrupted neuronal communication.</p> Signup and view all the answers

What was the outcome of the drug Aduhelm upon its approval?

<p>Aduhelm was approved but faced controversy for not demonstrating significant clinical efficacy, despite being able to remove amyloid plaques.</p> Signup and view all the answers

What is the function of tau proteins in a healthy brain, and how does it change in Alzheimer's Disease?

<p>Tau proteins stabilize microtubules in neurons, but become hyperphosphorylated in Alzheimer's, leading to disrupted function and neurofibrillary tangles.</p> Signup and view all the answers

How does apolipoprotein E (ApoE) relate to Alzheimer's Disease?

<p>ApoE, particularly the ApoE4 gene, is the most significant genetic risk factor for Alzheimer's, as it stabilizes Aβ oligomers and impairs their degradation.</p> Signup and view all the answers

What are the aims of treatments involved in the pharmacological approach toward Tau?

<p>The aims are to prevent tau aggregation or phosphorylation and to increase clearance of tau proteins from neurons.</p> Signup and view all the answers

What side effects were associated with drugs like Aduhelm and their treatment methods?

<p>Significant side effects include swelling and bleeding in the brain, which were observed in a notable percentage of patients.</p> Signup and view all the answers

How does the process of Aβ aggregation contribute to Alzheimer's pathology?

<p>Aβ aggregation forms oligomers that are neurotoxic, leading to synaptic loss, neuron death, and impaired neuronal communication.</p> Signup and view all the answers

What percentage of the population over 65 is affected by Alzheimer's Disease?

<p>Approximately 10% of the population over 65 is affected by Alzheimer's Disease.</p> Signup and view all the answers

What was the outcome of the drug Leqembi regarding its mechanism of action?

<p>Leqembi interferes with the formation of Aβ fibrils, aiming to prevent plaque accumulation.</p> Signup and view all the answers

What are the main effects of opioids on neurotransmitter release in the brain?

<p>Opioids inhibit GABA release, leading to increased dopamine levels in the nucleus accumbens.</p> Signup and view all the answers

How do psychomotor stimulants like cocaine and amphetamine affect neurotransmitter levels?

<p>They increase dopamine, serotonin, and norepinephrine levels by inhibiting their transporters.</p> Signup and view all the answers

What is the primary mechanism of action for MDMA?

<p>MDMA inhibits the transporters of dopamine, serotonin, and norepinephrine, increasing their levels.</p> Signup and view all the answers

What receptors are primarily associated with the effects of cannabis?

<p>Cannabis mainly interacts with CB1 and CB2 receptors in the brain and immune system.</p> Signup and view all the answers

Explain how amphetamine increases neurotransmitter availability.

<p>Amphetamine inhibits transporter degradation and induces the release of neurotransmitters via reverse transport.</p> Signup and view all the answers

Why are opioids considered generally inhibitory in their action?

<p>Opioids activate receptors that inhibit neurotransmitter release, mainly through GABA inhibition.</p> Signup and view all the answers

What symptoms might characterize stimulant use involving elevated norepinephrine?

<p>Symptoms include anxiety, rapid heart rate, and hypertension.</p> Signup and view all the answers

How does cannabis use influence emotional regulation according to its mechanism?

<p>Cannabis decreases activity in the amygdala, leading to better cognitive control of emotions.</p> Signup and view all the answers

What are the recreational names associated with both cocaine and amphetamine?

<p>Cocaine is known as coke, snow, and crack, while amphetamine is referred to as speed, crystal, and meth.</p> Signup and view all the answers

Describe the impact of opioids on pain perception.

<p>Opioids provide analgesia by modulating pain signals in the central nervous system.</p> Signup and view all the answers

What general behavioral symptoms are associated with stimulant drugs?

<p>Symptoms include euphoria, increased energy, and impulsive behavior.</p> Signup and view all the answers

What is the function of endocannabinoids in the central nervous system?

<p>Endocannabinoids act as agonists at cannabinoid receptors, regulating neurotransmitter release.</p> Signup and view all the answers

How does alcohol affect cognitive and motor functions?

<p>Alcohol impairs motor coordination and judgment, leading to slurred speech and reduced cognitive function.</p> Signup and view all the answers

What distinguishes the physiological effects of cannabis from those of opioids?

<p>Cannabis typically induces relaxation and altered perception, while opioids primarily provide pain relief and euphoria.</p> Signup and view all the answers

What is the result of excessive degradation of acetylcholine in Alzheimer's disease?

<p>Impaired memory</p> Signup and view all the answers

Excessive glutamate in synapses can lead to neuronal death.

<p>True</p> Signup and view all the answers

Name the enzyme that initiates pathological amyloid plaque formation.

<p>β-Secretase</p> Signup and view all the answers

Drugs like donepezil and galantamine inhibit the enzyme _____ to increase acetylcholine levels.

<p>AChE</p> Signup and view all the answers

Match the following neurotransmitter issues with their corresponding pharmacological approach:

<p>Low ACh = AChE inhibitors (donepezil) Excessive glutamate = NMDA channel blockers (memantine)</p> Signup and view all the answers

What is the primary effect of β-amyloid on nmDA receptors?

<p>Enhances receptor activation</p> Signup and view all the answers

Current treatments for Alzheimer’s disease significantly modify the disease's progression.

<p>False</p> Signup and view all the answers

What is the major focus of current clinical trials regarding Alzheimer's disease?

<p>Disease modification</p> Signup and view all the answers

What is the role of ghrelin in the body?

<p>Stimulates hunger</p> Signup and view all the answers

Alcohol decreases the release of glutamate, resulting in less excitation.

<p>True</p> Signup and view all the answers

What neurotransmitter's release is enhanced by β-endorphin due to alcohol consumption?

<p>Dopamine</p> Signup and view all the answers

Alcohol enhances GABA actions by acting as a ______ of GABA A receptors.

<p>positive allosteric modulator</p> Signup and view all the answers

Match the following mechanisms with their effects of alcohol:

<p>Enhances GABA Actions = Increased inhibition of neurons Decreases Glutamate Release = Reduced neuronal excitation Enhances Opioid System = Increased dopamine in NAc Interferes with Neuronal Structure = Membrane deformation</p> Signup and view all the answers

Which effect does alcohol have on olfactory sensitivity?

<p>Increases sensitivity to food smells</p> Signup and view all the answers

Alcohol's action on the amygdala is primarily associated with increasing aversive activity.

<p>False</p> Signup and view all the answers

What specific effect does alcohol have on GABA neurons in the Ventral Tegmental Area (VTA)?

<p>Inhibits GABA neurons</p> Signup and view all the answers

What is one of the primary pathological features of Alzheimer's Disease?

<p>Formation of β–amyloid (Aβ) plaques</p> Signup and view all the answers

Aduhelm was approved for its proven efficacy in cognitive improvement.

<p>False</p> Signup and view all the answers

What age group has the highest prevalence of Alzheimer's Disease?

<p>Older than 85</p> Signup and view all the answers

The ____ proteins stabilize microtubules in neurons, playing a crucial role in neuronal function.

<p>tau</p> Signup and view all the answers

Match the following drugs with their action:

<p>Aduhelm = Binds to amyloid plaques Leqembi = Interferes with Aβ fibril formation Kisunla = Clears amyloid plaques Tramiprosate = Prevents Aβ42 aggregation</p> Signup and view all the answers

Which of the following treatments is focused on modifying the disease process rather than just symptoms?

<p>DMT (disease modifying therapies)</p> Signup and view all the answers

Aβ42 is considered a non-pathogenic subtype of amyloid.

<p>False</p> Signup and view all the answers

Which gene is identified as the most significant genetic risk factor for Alzheimer's Disease?

<p>ApoE4</p> Signup and view all the answers

Neurons in the ____ and ____ are often impacted first in Alzheimer's Disease.

<p>entorhinal cortex, hippocampus</p> Signup and view all the answers

What is the role of Apolipoprotein E (ApoE) in Alzheimer's disease?

<p>Stabilizes Aβ oligomers</p> Signup and view all the answers

Neurofibrillary tangles are formed due to the aggregation of β–amyloid plaques.

<p>False</p> Signup and view all the answers

What is one of the common approaches in treating tau aggregation in Alzheimer's Disease?

<p>Kinase inhibitors</p> Signup and view all the answers

Increasing blood flow through capillaries can cause ____ in patients under treatment for Alzheimer's disease.

<p>swelling/bleeding</p> Signup and view all the answers

Match the following phases of clinical trials with their corresponding actions:

<p>Phase 2 = Testing efficacy and side effects Phase 3 = Large-scale trials for effectiveness Phase 1 = Safety and dosage determination Phase 4 = Post-marketing surveillance</p> Signup and view all the answers

What neurotransmitters are increased by both cocaine and amphetamine?

<p>Dopamine, Norepinephrine, Serotonin</p> Signup and view all the answers

Amphetamine and cocaine have opposing effects on serotonin levels.

<p>False</p> Signup and view all the answers

Which receptor type is primarily associated with THC effects in the brain?

<p>CB1</p> Signup and view all the answers

The use of opioids can lead to increased levels of _____ in the nucleus accumbens (NAc).

<p>dopamine</p> Signup and view all the answers

Which of the following is NOT a common recreational name for cocaine?

<p>Crank</p> Signup and view all the answers

Match the following drugs with their corresponding effects:

<p>Cocaine = Euphoria and increased dopamine MDMA = Anxiolysis and enhanced emotionality Alcohol = Sedation and impaired motor coordination Opioids = Pain reduction and analgesia</p> Signup and view all the answers

MDMA primarily enhances dopamine and norepinephrine levels.

<p>True</p> Signup and view all the answers

What is the role of GABA in relation to dopamine release when opioids are administered?

<p>Inhibition</p> Signup and view all the answers

Cannabis (THC) primarily binds to _____ receptors.

<p>CB1 and CB2</p> Signup and view all the answers

What mechanism allows amphetamine to increase neurotransmitter availability?

<p>Inhibiting degradation and promoting reverse transport</p> Signup and view all the answers

Cannabis use can lead to emotional dysregulation due to its action on CB1 receptors.

<p>False</p> Signup and view all the answers

Name one common behavioral symptom associated with psychomotor stimulant use.

<p>Euphoria</p> Signup and view all the answers

The primary action of opioids is _____, which alters pain perception.

<p>analgesia</p> Signup and view all the answers

Which neurotransmitter is more strongly influenced by MDMA compared to cocaine?

<p>Serotonin</p> Signup and view all the answers

Study Notes

Alzheimer’s Disease: Brain Changes

  • Significant brain size reduction due to cellular loss.
  • Widespread neuronal dysfunction and death.
  • Loss of connections between neurons disrupts communication.
  • Memory areas like the entorhinal cortex and hippocampus are affected first.
  • Cerebral cortex areas responsible for language, reasoning, and social behavior are impacted later.
  • Gradually, patients lose the ability to live and function independently.
  • Current treatments focus on symptom relief for cognitive function and delaying cognitive decline.
  • No current medication can stop or reverse the disease's progression.

Alzheimer’s Disease: Prevalence and Pathological Features

  • A form of dementia: most common.
  • 10% of the population above 65 years of age is affected.
  • 50% of people older than 85 years of age are affected.
  • Two noticeable features: β–amyloid (Aβ) plaques and neurofibrillary tangles (hyperphosphorylation of the tau protein).
  • Most drug development efforts focus on preventing or breaking down these features (mostly Aβ).

Alzheimer’s Disease: Investigative Treatments in 2024

  • Most treatments focus on modifying the disease.
  • 65% of Phase 3 clinical trials in 2024 focused on disease-modifying therapies.
  • Other trials aim for symptom relief.
  • 32 potential drugs are being evaluated in Phase 3 trials, with another 81 in Phase 2.

Key Factors in Alzheimer’s Disease: Normal Enzymatic Degradation

  • β–amyloid (Aβ) is a fragment of a larger protein, the β-amyloid precursor protein (APP), found in the neuronal membrane.
  • APP is cleaved by different enzymes.
  • The initial cut by α-secretase results in the sAPPα peptide.
  • The subsequent cut by -secretase results in the P3 peptide.
  • This normal processing does not lead to plaque formation.

Key Factors in Alzheimer’s Disease: Aβ Formation

  • The first cut by β-secretase results in the sAPPβ peptide.
  • The following cut by -secretase results in Aβ.
  • The position of the -secretase cut determines the pathogenicity of the Aβ peptide.
  • Aβ42 (long) is the pathogenic subtype that leads to amyloid plaque formation.

Key Factors in Alzheimer’s Disease: Aβ Oligomers, Fibrils, and Amyloid Plaques

  • Aβ oligomers are collections of Aβ42 fragments before plaque formation.
  • Some oligomers misfold, causing others to do the same.
  • Misfolding facilitates aggregation leading to amyloid plaque formation.
  • Aβ oligomers, fibrils, and amyloid plaques damage neuronal membranes, leading to neuron death and synaptic loss.
  • Plaques interfere with neuronal communication.

Failed Approaches for Pharmacological Treatment of AD

  • Modulation of enzymes has not been successful.
  • Semagacestat inhibits  secretase.
  • Tarenflurbil shifts the cleavage site.
  • Verubecestat, Atabecestat, and Lanabecestat β-secretase (BACE1) inhibitors have failed and may worsen cognition.

Approaches for Pharmacological Treatment: Aβ

  • Prevent Aβ42 aggregation by making it less 'sticky'.
  • Tramiprosate, designed to bind to Aβ42 and prevent the formation of plaques, failed in Phase 3 trials.
  • Clear Aβ oligomers.
  • Upregulate Aβ 'transport proteins' like P-glycoprotein and LRP1 to remove Aβ from the brain.
  • Immunize for Aβ42 or the plaques.

Recent News: Aduhelm

  • Aduhelm was approved in June 2021 for patients with mild cognitive impairment or mild dementia.
  • A monoclonal antibody that targets aggregated forms of amyloid plaques.
  • Believed to clear plaques from the brain or lead to glial cells digesting amyloid.
  • There is controversy as the drug did not show greater efficacy than the placebo group.
  • Approved based on plaque reduction.
  • Concerns about MRI abnormalities observed in 41% of patients.
  • Drug discontinued in 2024.

Recent News: Leqembi and Kisunla

  • Leqembi (lecanemab) was approved in May 2022 for patients with mild cognitive impairment or mild dementia.
  • A monoclonal antibody that interferes with the formation of Aβ fibrils.
  • Kisunla (donanemab) was approved in July 2024.
  • A monoclonal antibody that works similarly to Aduhelm but may clear more plaques.
  • Early treatment is important to clear plaques and reduce further damage.
  • Significant side effects include swelling and bleeding in the brain.

Key Factors in Alzheimer’s Disease: Apolipoprotein E (ApoE)

  • Produced by microglia.
  • The ApoE4 gene is the most significant genetic risk factor identified for AD.
  • Stabilizes Aβ oligomers, impairs degradation, and enhances -secretase activity.

Key Factors in Alzheimer’s Disease: Tau Proteins

  • Stabilize microtubules and aid in tubulin assembly.
  • Become hyperphosphorylated in AD, disrupting their normal function.

Key Factors in Alzheimer’s Disease: Tau Proteins

  • Disrupted microtubule function interferes with transport of synaptic vesicles.
  • Neurofibrillary tangles, accumulations of tau proteins, form inside neurons, disrupting neuronal function and leading to death.

Approaches for Pharmacological Treatment: Tau

  • Prevent Tau aggregation or phosphorylation.
  • AADvac1 & 2, Semorinemab, LMTM, and ABBV-8E12 are examples of vaccines, molecules, and antibodies in development.
  • Kinase inhibitors to prevent phosphorylation are being explored in preclinical research..

Alzheimer’s Disease: Transmitters - ACh

  • ACh is an important neurotransmitter in learning and memory.
  • One of the first systems impacted in AD.
  • Low ACh levels are found in AD due to excessive degradation by acetylcholinesterase (AChE).
  • Impairs memory.

Alzheimer’s Disease: Transmitters - Glutamate

  • Excessive glutamate in synapses due to dysfunction of reuptake proteins and degradation enzymes.
  • This may be caused by β amyloid.
  • Over-activation of NMDA receptors leads to high influx of Ca2+, which is cytotoxic and leads to neuronal death.

Approaches for Pharmacological Treatment: Neurotransmitters

  • Inhibit AChE to increase ACh.
  • Examples: donepezil, galantamine.
  • Block NMDA channels to limit Ca2+ influx.
  • Example : memantine.
  • These treatments have modest and temporary effects on symptoms.

Take-home Message

  • Alzheimer’s disease is a progressive disorder caused by several factors, including pathological aggregations, atypical inflammation, and neurotransmitter abnormalities.
  • Current treatments are limited and temporary in their effects on symptoms.
  • Disease-modifying therapies are the focus of ongoing research and clinical trials.
  • The possibility of treating patients too late in the disease progression requires careful evaluation.

Drugs and their associated effects

  •  Cocaine increases dopamine, serotonin and norepinephrine levels in the brain by inhibiting their respective transporters.
  •  Amphetamine increases dopamine, serotonin, and norepinephrine levels in the brain by inhibiting transporters, inhibiting degradation, and inducing release.
  •  MDMA increases dopamine, serotonin, and norepinephrine levels in the brain by inhibiting transporters, but has the strongest influence on serotonin transporters.
  •  Opioids bind to various opioid receptors, predominantly mu, delta, kappa, and nociceptin.
  •  Opioids are primarily inhibitory, acting primarily presynaptically.
  •  Cannabis is a psychoactive drug containing THC, which binds to the CB1 and CB2 receptors.
  •  Cannabis primarily acts as an inhibitor by reducing acetylcholine, serotonin, GABA, and glutamate.
  •  Alcohol is a widely used psychoactive drug that affects various neurotransmitter systems.
  •  The mechanism of action of alcohol is complex, but it is known to enhance GABA action and reduce glutamate excitation.
  •  MDMA decreases activity in the amygdala, the region of the brain that processes emotions, leading to reduced fear and anxiety.

Opioid Mechanisms

  •  Opioids like morphine inhibit GABA release in the VTA, which further reduces dopamine release in the NAc.
  •  Opioid receptors are found throughout the brain, notably in the reward and pain centers.

Alcohol Mechanisms

  •  Alcohol can enhance GABA effects and reduce glutamate excitation.
  •  The drug stimulates increased β-endorphin release, leading to increased dopamine levels in the NAc, similar to the effects of morphine.
  •  Alcohol can affect neuronal structure and function.

Alzheimer’s Disease

  • Alzheimer’s Disease is a progressive neurodegenerative disease, the most common form of dementia.
  • It involves a significant decline in brain size due to neuronal loss and disruption of neuronal communication.
  • The entorhinal cortex and hippocampus, involved in memory, are affected first.
  • It progresses to the cerebral cortex, affecting language, reasoning, and social behavior.
  • Current treatments focus on managing symptoms, with limited success in halting or reversing the disease progression.

Prevalence

  • 10% of the population over 65 years old are affected by Alzheimer's Disease.
  • This number increases to 50% in individuals over 85.

Pathological Features

  • Two major hallmarks are amyloid-beta (Aβ) plaques and neurofibrillary tangles.
  • Aβ plaques are formed by the aggregation of Aβ42 fragments, a product of APP cleavage.
  • Neurofibrillary tangles are formed by the accumulation of hyperphosphorylated tau proteins, disrupting microtubule function.

Aβ Formation and Aggregation

  • Aβ is a fragment of the larger protein APP, which is located in the neuronal membrane and regulates synapse formation.
  • APP is cleaved by different enzymes: α-secretase, β-secretase, and γ-secretase.
  • α-secretase cleavage does not lead to plaque formation.
  • β-secretase cleavage initiates the formation of Aβ.
  • The position of γ-secretase cleavage determines if Aβ is pathological or not.
  • Aβ42, a longer subtype of Aβ, is considered the pathogenic one.
  • Aβ oligomers, misfolded collections of Aβ42 fragments, can act as infectious agents, facilitating plaque formation.

Aβ Toxicity

  • Aβ oligomers, fibrils, and plaques damage neuronal membranes and interfere with neuronal communication.
  • They disrupt ion channels, ion flow, receptors, and synaptic communication, leading to synaptic loss and neuronal death.

Failed Treatments Targeting Aβ

  • Semagacestat, an inhibitor of γ-secretase, failed to show efficacy.
  • Tarenflurbil, aiming to shift the cleavage site, also failed to achieve desired results.
  • β-secretase (BACE1) inhibitors, including Verubecestat, Atabecestat, and Lanabecestat, failed and potential worsen cognition.

Current Approaches Targeting Aβ

  • Preventing Aβ42 aggregation by interfering with its binding and plaque formation (e.g., Tramiprosate failed in phase 3).
  • Clearing Aβ oligomers by upregulating Aβ transport proteins (P-glycoprotein, LRP1) to remove it from the brain.
  • Immunizing against Aβ42 or plaques to trigger the immune system to attack them.

Aduhelm (aducanumab)

  • Approved in June 2021 for mild cognitive impairment or mild dementia stages.
  • A monoclonal antibody that binds to aggregated forms of amyloid plaques.
  • Believed to clear plaques from the brain or facilitate their removal by glial cells.
  • Controversy surrounds its efficacy, as it did not show significant improvement compared to placebo.
  • Approved based on plaque reduction rather than clinical improvement.
  • Significant side effects include swelling and bleeding in the brain, occurring in 41% of patients.
  • The drug was discontinued in 2024.

Leqembi (lecanemab)

  • Approved in May 2022 for mild cognitive impairment or mild dementia stages.
  • A monoclonal antibody that interferes with the formation of Aβ fibrils.

Kisunla (donanemab)

  • Approved in July 2024.
  • A monoclonal antibody similar to Aduhelm, but may clear more plaques.

Apolipoprotein E (ApoE)

  • Produced by microglia.
  • The ApoE4 gene is the most significant genetic risk factor for AD identified so far.
  • ApoE4 stabilizes Aβ oligomers, impairs their degradation, and enhances γ-secretase activity.
  • Potential treatment strategies include neutralizing it with antibodies, degrading it, or transporting it out of the brain.

Tau Proteins

  • Stabilize microtubules and aid in their assembly.
  • Become hyperphosphorylated in AD, disrupting their normal function.
  • This disruption leads to impaired microtubule transport function, particularly of synaptic vesicles.
  • Neurofibrillary tangles, accumulations of tau proteins, form within neurons and further disrupt neuronal function.

Approaches Targeting Tau

  • Prevent Tau aggregation or phosphorylation: AADvac1 & 2, Semorinemab, LMTM (failed), ABBV-8E12 (failed) - vaccines, molecules, or antibodies that prevent aggregation and/or increase clearance (some in phase 2 and 3).
  • Kinase inhibitors to prevent phosphorylation (preclinical stage).

Neurotransmitters in Alzheimer's Disease

  • Acetylcholine (ACh):

    • ACh is vital for learning and memory in the hippocampus and other brain regions.
    • One of the first systems affected in AD.
    • Low ACh levels are observed due to its excessive degradation by acetylcholinesterase (AChE).
    • This leads to impaired memory function.

  • Glutamate:

    • Excessive glutamate in synapses occurs due to dysfunction of reuptake proteins and degradation enzymes.
    • This over-activation of NMDA receptors causes a high influx of Ca2+, which is toxic to neurons and triggers neuronal death.

Approaches Targeting Neurotransmitters

  • Targeting ACh: Inhibiting AChE to increase ACh using donepezil and galantamine.
  • Targeting Glutamate: Blocking NMDA channels to limit Ca2+ influx using memantine.

Summary

  • Alzheimer's Disease is a progressive neurodegenerative disorder resulting from neuronal dysfunction and death.
  • This is caused by pathological protein aggregations (Aβ and tau), inflammation, neurotransmitter abnormalities, and potential association with age-related ailments.
  • Current treatments have minimal and temporary effects on symptoms while disease-modifying therapies are the focus of ongoing research.
  • Early intervention may prove crucial, as current treatments may be ineffective if administered too late in the disease progression.

Drugs of Abuse

  • Opioids are a class of drugs that act on opioid receptors in the brain.

    • Opioid receptors are G-protein coupled receptors (metabotropic).
    • There are four main types of opioid receptors: mu (µ), delta (δ), kappa (κ) and sigma (σ).
    • Opioid receptors are found throughout the nervous system, but they are particularly concentrated in areas involved in reward and pain.
    • Most opioid ligands bind to multiple opioid receptors, but with different affinities and potencies.
    • There are four propeptides that give rise to different opioid peptides: Pro-opiomelanocrtin (POMC), proenkephalin, prodynorphin and pronociceptin.
    • The opioid receptor system is mostly inhibitory.
    • Opioids act presynaptically by inhibiting GABA release.
    • GABA is an inhibitory neurotransmitter, therefore inhibiting GABA release in the VTA removes a “brake” on dopamine release by the mesolimbic pathway, thus ultimately leading to increased dopamine levels in the NAc.

  • Psychomotor Stimulants increase dopamine, serotonin and norepinephrine signaling in the brain.

    • Cocaine binds to the transporters of these neurotransmitters and inhibits reuptake, thereby increasing their concentration in the synapse.
    • Amphetamine inhibits the transporters, inhibits degradation of the neurotransmitters by MAO, and induces release of dopamine, serotonin, and norepinephrine from the presynaptic neuron.
    • The mechanism of action of amphetamine ultimately results in a massive increase in the concentration of dopamine, serotonin and norepinephrine in the synaptic cleft.
    • Each of these neurotransmitters has a different profile of behaviors.

  • Methylenedioxymethamphentamine (MDMA) is a derivative of amphetamine that increases dopamine, serotonin and norepinephrine signaling.

    • MDMA has a stronger affinity for the serotonin transporter relative to the other two transporters
    • MDMA decreases activity in the amygdala.
    • Negative affect has been associated with increased activity in the amygdala, therefore MDMA decreases negative affect.

  • Cannabis is a psychoactive drug that contains tetrahydrocannabinol (THC).

    • THC acts on cannabinoid receptors in the brain, particularly CB1 and CB2 receptors.
    • CB1 receptors are mainly found on presynaptic neurons and are inhibitory heteroreceptors.
    • CB1 receptors influence the release of other neurotransmitters like acetylcholine, serotonin, GABA and glutamate.
    • There are several endogenous agonists for cannabinoid receptors, including anandamide and 2-arachidonoylglycerol (2-AG).
    • CB1 receptors are expressed in many CNS sites and are diverse.
    • CB1 receptors are found in the reward pathway, and influence dopamine release both directly and indirectly.
    • Cannabis also appears to increase the release of the hormone ghrelin, thereby increasing appetite.

  • Alcohol is a depressant that acts on several different neurotransmitter systems.

    • Alcohol is known to enhance the effects of GABA by acting as a positive allosteric modulator of GABA-A receptors.
    • Alcohol decreases glutamate-related excitation by inhibiting glutamate release in a presynaptic mechanism and by inhibiting the action of AMPA and NMDA receptors.
    • Alcohol enhances opioid system activity by causing β-endorphin release, resulting in increased DA in the NAc.
    • Alcohol disrupts neuronal structure and function by interfering with neuronal lipid membranes and by interfering with second-messenger systems.

  • MDMA is the drug with a strong association with decreasing aversive activity in the amygdala.

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