Alzheimer's Disease Overview
40 Questions
1 Views

Alzheimer's Disease Overview

Created by
@AchievableSalamander

Podcast Beta

Play an AI-generated podcast conversation about this lesson

Questions and Answers

Which brain areas are primarily impacted first in Alzheimer's Disease?

  • Amygdala and thalamus
  • Cerebral cortex and language centers
  • Entorhinal cortex and hippocampus (correct)
  • Frontal lobe and occipital lobe

    • What is the most common form of dementia in older adults?

  • Frontotemporal dementia
  • Lewy body dementia
  • Vascular dementia
  • Alzheimer's Disease (correct)

    • What are the pathologically noticeable features of Alzheimer's Disease?

  • Neurotic plaques and synaptic neurofibrillary tangles
  • Tau tangles and beta-amyloid plaques (correct)
  • Protein aggregation and myelin degeneration
  • Astrocytic alterations and ventricular enlargement

    • What treatment approaches primarily account for the majority of Alzheimer's Disease clinical trials?

    <p>Disease modifying therapies</p> Signup and view all the answers

    Which protein is implicated as a significant genetic risk factor for Alzheimer's Disease?

    <p>Apolipoprotein E (ApoE)</p> Signup and view all the answers

    What is the main function of tau proteins in neurons?

    <p>Stabilize microtubules</p> Signup and view all the answers

    What is the purpose of ApoE in the context of Alzheimer's Disease?

    <p>Stabilize beta-amyloid oligomers</p> Signup and view all the answers

    Which drug was controversially approved despite failing to show efficacy above the placebo group?

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

    What type of agents have most of the failed pharmacological treatments for Alzheimer's focused on?

    <p>Enzyme modulators</p> Signup and view all the answers

    What does the β-secretase enzyme cut to contribute to the formation of pathogenic Aβ?

    <p>Beta-amyloid precursor protein (APP)</p> Signup and view all the answers

    Which enzyme is responsible for initiating the formation of pathological amyloid plaques?

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

    What neurotransmitter is primarily affected early in Alzheimer's disease?

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

    What is one way pharmacological treatment attempts to address the neurotransmitter issue in Alzheimer's disease?

    <p>Inhibit acetylcholinesterase</p> Signup and view all the answers

    What is a consequence of excessive glutamate in the synapses?

    <p>Over-activation of NMDA receptors</p> Signup and view all the answers

    What is a common therapeutic approach for treating Alzheimer's disease symptoms?

    <p>Memantine to block NMDA channels</p> Signup and view all the answers

    Which statement about current Alzheimer's disease treatments is accurate?

    <p>They have minor and temporary effects on symptoms.</p> Signup and view all the answers

    What causes cytotoxicity in neurons associated with Alzheimer's disease?

    <p>High levels of calcium influx</p> Signup and view all the answers

    What condition is one of the first neurotransmitter systems to be affected in Alzheimer's disease?

    <p>Acetylcholine system</p> Signup and view all the answers

    What is a potential reason for the limited success of disease-modifying therapies in Alzheimer's?

    <p>Patients are treated too late.</p> Signup and view all the answers

    Which factor is associated with neuronal death in Alzheimer's disease?

    <p>Atypical inflammation</p> Signup and view all the answers

    What neurotransmitter does morphine inhibit through GABA release?

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

    Which drug primarily increases activity in serotonin transporters?

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

    Which receptor is primarily involved in the effects of THC in the central nervous system?

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

    What is one potential effect of cocaine use on neurotransmitter levels?

    <p>Increased norepinephrine levels</p> Signup and view all the answers

    What class of drugs does cannabis primarily belong to?

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

    Which symptom is commonly associated with the use of amphetamines?

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

    Which system does opioids heavily affect due to receptor concentration?

    <p>Mesolimbic system</p> Signup and view all the answers

    What is a common psychological effect of cannabis use?

    <p>Increased paranoia</p> Signup and view all the answers

    Which of the following drugs primarily leads to euphoria through the elevation of dopamine levels?

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

    What is a physiological effect of opioids on respiration?

    <p>Mild respiratory depression</p> Signup and view all the answers

    What hormone is released from the stomach to stimulate hunger?

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

    How does alcohol affect glutamate activity?

    <p>Decreases glutamate release</p> Signup and view all the answers

    Which neurotransmitter's actions are enhanced by alcohol through positive allosteric modulation?

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

    What is the effect of β-endorphin release in the presence of alcohol?

    <p>Increased dopamine levels in the nucleus accumbens</p> Signup and view all the answers

    Alcohol interferes with which of the following neuronal structures?

    <p>Neuronal lipid membranes</p> Signup and view all the answers

    What effect does alcohol have on the hypothalamus regarding hunger and satiety?

    <p>Increases hunger stimulation</p> Signup and view all the answers

    How does alcohol influence the opioid system?

    <p>Enhances β-endorphin release</p> Signup and view all the answers

    What mechanism reduces glutamate release when alcohol is consumed?

    <p>Inhibition at mGluR autoreceptors</p> Signup and view all the answers

    Which of the following describes the action of alcohol on neuronal function?

    <p>Deforms neuronal lipid membranes</p> Signup and view all the answers

    What is a significant effect of alcohol on the amygdala regarding aversive activities?

    <p>Decreases aversive activity</p> Signup and view all the answers

    Study Notes

    Alzheimer's Disease

    • Alzheimer's disease (AD) is a progressive disorder that leads to significant neuronal dysfunction and death.
    • AD is the most common form of dementia, affecting 10% of individuals over 65 years old and 50% of those over 85.
    • AD is characterized by two prominent pathological features: β-amyloid (Aβ) plaques and neurofibrillary tangles (hyperphosphorylated tau proteins).

    Key Factors in Alzheimer's Disease

    • β-amyloid (Aβ) is a fragment of a larger protein called amyloid precursor protein (APP).
    • APP is a key regulator of synapse formation and is located in the neuronal membrane.
    • APP is cleaved by various enzymes.
    • Normal APP processing involves α-secretase, which cleaves APP, resulting in sAPPα peptide and a remaining protein fragment that is cleaved by ɣ-secretase to form P3 peptide, which does not lead to plaque formation.

    Aβ Formation

    • Pathological Aβ formation occurs through a different cleavage pathway involving β-secretase, followed by ɣ-secretase.
    • This process leads to the production of Aβ peptides, which are prone to aggregation.
    • The exact position of the ɣ-secretase cut determines whether the generated Aβ peptide is pathogenic or not.
    • Aβ42, the longer form of Aβ, is considered the most pathogenic, leading to amyloid plaque formation.

    Aβ Oligomers

    • Aβ42 fragments can misfold and form oligomers.
    • Aβ oligomers can act as prions, which can lead to the misfolding of other Aβ molecules, accelerating aggregation and plaque formation.
    • Aβ oligomers, fibrils, and amyloid plaques can damage neuronal membranes and cause neurotoxicity.
    • They disrupt neuronal communication by interfering with ion channels, ion flow, receptors, and synaptic communication.

    ApoE

    • Apolipoprotein E (ApoE) is a protein produced by microglia and is a major genetic risk factor for AD.
    • The ApoE4 gene is particularly associated with an increased risk of AD.
    • ApoE4 stabilizes Aβ oligomers, impairs their degradation, and enhances the activity of ɣ-secretase.

    Tau Proteins

    • Tau proteins help stabilize microtubules and aid the assembly of tubulin.
    • In AD, tau proteins become hyperphosphorylated, disrupting their normal function.
    • The loss of tau protein function leads to microtubule instability, disrupting the transport of synaptic vesicles.
    • The accumulation of hyperphosphorylated tau proteins forms neurofibrillary tangles inside neurons, contributing to neuronal dysfunction and death.

    AD: Investigative Treatments in 2024

    • A growing number of clinical trials are focusing on disease-modifying therapies (DMTs) for AD.
    • DMTs account for 65% of phase 3 trials in 2024.
    • As of 2024, 32 potential drugs are being evaluated in phase 3 clinical trials, with another 81 in phase 2.
    • Recent years have also seen an increase in therapies focused on managing the symptoms of AD.

    Failed Pharmacological Approaches for AD

    • Numerous drug trials have failed in their attempt to modulate the enzymes involved in Aβ formation.
    • Semagacestat, an inhibitor of ɣ-secretase, and Tarenflurbil, a drug that aimed to shift the cleavage site, both failed.
    • β-secretase (BACE1) inhibitors, including Verubecestat, Atabecestat, and Lanabecestat, have also failed and may even worsen cognitive function.

    Pharmacological Approaches for Aβ

    • Current research explores various strategies to target Aβ:
      • Preventing Aβ42 aggregation: Binding to Aβ42 to interfere with its aggregation (Tramiprosate failed in phase 3).
      • Clearing out Aβ oligomers: Preventing plaque formation by upregulating Aβ “transport proteins” like P-glycoprotein and LRP1 to remove Aβ from the brain.
      • Immunization against Aβ42 or plaques: Utilizing the immune system to target Aβ42 or the plaques for removal.

    Aduhelm

    • Aduhelm (aducanumab) was approved in June 2021 for patients with mild cognitive impairment or mild dementia stage of AD.
    • Aduhelm is a monoclonal antibody that binds to aggregated forms of amyloid plaques.
    • It is believed to clear plaques from the brain or facilitate their digestion by glial cells.
    • Despite plaque removal, clinical improvement was not consistently observed.
    • Concerns arose regarding its effectiveness and side effects.
    • Aduhelm was subsequently discontinued in 2024.

    Leqembi and Kisunla

    • Leqembi (lecanemab), approved in May 2022, is a monoclonal antibody that interferes with the formation of Aβ fibrils.
    • Kisunla (donanemab), approved in July 2024, is a monoclonal antibody similar to Aduhelm but may clear more plaques.
    • Both therapies require early intervention for optimal efficacy, with the potential to be discontinued when plaques are cleared until their reappearance.
    • Significant side effects, such as swelling and bleeding in the brain, continue to present challenges.

    Pharmacological Approaches for Tau

    • Research aims to prevent tau aggregation and phosphorylation through various approaches:
      • AADvac1 & 2, Semorinemab, LMTM, and ABBV-8E12: These vaccines, molecules, and antibodies are being investigated for their ability to prevent tau aggregation and/or enhance clearance.
      • Kinase inhibitors: These drugs target kinases that phosphorylate tau proteins, preventing the hyperphosphorylation process and the formation of neurofibrillary tangles.

    Neurotransmitter Abnormalities in AD

    • Acetylcholine (ACh) levels decline in AD, affecting learning and memory processes, particularly in the hippocampus.
    • Low ACh levels are attributed to the excessive degradation of ACh by acetylcholinesterase (AChE).
    • Glutamate levels become excessive in synapses, due to dysfunction of reuptake proteins and degradation enzymes, both potentially caused by Aβ.
    • This glutamate over-activation leads to an excessive influx of calcium ions (Ca2+) through NMDA receptors, which is cytotoxic and contributes to neuronal death.

    Pharmacological Approaches for NTs

    • Strategies to manage neurotransmitter abnormalities in AD include:
      • Inhibiting AChE to increase ACh levels (donepezil, galantamine).
      • Blocking NMDA channels to limit Ca2+ influx (memantine).
    • These approaches provide temporary symptomatic relief but do not modify the underlying disease process.

    Conclusion

    • AD is a multifaceted disease, involving neuronal dysfunction, death, amyloid plaque formation, tau protein abnormalities, neurotransmitter imbalances, and other age-related ailments.
    • Current treatment options primarily manage symptoms, providing temporary relief.
      • DMTs are the primary focus of ongoing research and recently approved drugs.
    • The need for early intervention with DMTs raises questions about whether patients are being treated too late in the disease progression.

    Opioids

    • Opioids are a group of psychoactive drugs with different effects on the brain.
    • They bind to G-coupled (metabotropic) receptors including mu (µ1 and µ2), delta (δ), kappa (κ), and opioid-like/nociceptin/orphanin FQ/sigma (σ, OFQ, NOP-R ).
    • Most opioid ligands bind to multiple opioid receptors, except for the NOP-R.
    • They originate from four propeptides:
      • pro-opiomelanocrtin (POMC),
      • proenkephalin,
      • prodynorphin,
      • pronociceptin

    Opioid Effects

    • Opioids have a general inhibitory effect, acting primarily on presynaptic neurons.
    • Presynaptically, they inhibit GABA release in the VTA, by removing a "brake" on dopamine (DA) release in the NAc via the mesolimbic pathway.
    • This leads to increased dopamine levels in the NAc, contributing to feelings of pleasure and reward.
    • Opioids are found throughout the nervous system with a high concentration in areas related to reward and pain.

    Cocaine

    • Cocaine is a stimulant drug that increases the levels of dopamine, serotonin, and norepinephrine in the brain.
    • It binds to and inhibits the reuptake transporters for these neurotransmitters, leading to an accumulation of these neurochemicals in the synaptic cleft.
    • This results in increased neurotransmitter activity, causing various effects like euphoria, heightened alertness, and increased energy.

    Amphetamine

    • Amphetamine is another stimulant drug that increases the levels of dopamine, serotonin, and norepinephrine in the brain.
    • It inhibits the reuptake transporters for these neurotransmitters, similarly to cocaine.
    • It also inhibits the degradation of these transmitters by MAO (Monoamine oxidase), and induces their release by reversing the reuptake process.
    • This leads to a much greater increase in neurotransmitter activity compared to cocaine.
    • These effects result in increased alertness, energy, and mood elevation, but also lead to potential adverse effects like anxiety, paranoia, and addiction.

    Methylenedioxymethamphentamine (MDMA)

    • A derivative of amphetamine, MDMA (ecstasy, molly) also elevates levels of dopamine, serotonin, and norepinephrine.
    • It acts primarily on serotonin transporters which are inhibited, leading to increased serotonin levels in the brain.
    • It reduces activity in the amygdala, contributing to reduced fear and anxiety.

    Cannabis (THC)

    • THC is the psychoactive component of Cannabis.
    • It interacts with CB1 and CB2 receptors (metabotropic) within the brain.
    • CB1 receptors are mainly found on presynaptic neurons, acting as heteroreceptors and inhibiting the release of neurotransmitters such as ACh, 5-HT, GABA, and glutamate.
    • CB2 receptors are primarily located on non-neuronal cells like immune cells.
    • Endogenous lipids like anandamide and 2-arachidonoylglycerol (2-AG) act as agonists for these receptors.
    • The CB1 receptor activation in the VTA can either increase or decrease dopamine release in the NAc by inhibiting GABA or glutamate release respectively.

    Alcohol (Ethanol)

    • Alcohol acts on a wide range of neurotransmitters and systems and its mechanisms are complex.
    • Enhanced GABA Actions: Alcohol binds to GABA-A receptors as a positive allosteric modulator (PAM), leading to increased inhibition (Cl- influx) and a reduction in neuronal excitation.
    • Reduced Glutamate Excitation: Alcohol decreases glutamate release by pre-synaptic action and inhibits post-synaptic ionotropic glutamate receptors (AMPA and NMDA), resulting in less glutamate activity and less excitation.
    • Enhanced Opioid System: Alcohol increases β-endorphin release, leading to increased dopamine in the NAc similar to the effects of morphine.
    • Neuronal Structure/Function: Alcohol interferes with neuronal lipid membranes, causing membrane deformation but also disturbs 2nd messenger systems by stimulating G-proteins.

    MDMA/Amygdala/Negative Affect

    • Strong evidence suggests that MDMA has a significant association with decreasing aversive activity in the amygdala, a brain region heavily involved in emotional processing, particularly fear and anxiety.
    • MDMA's effect on serotonin transporters leads to increased serotonin levels in the amygdala, which has shown a significant role in reducing negative emotional responses.

    Studying That Suits You

    Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

    Quiz Team

    Related Documents

    Alzheimer's Disease Lecture Notes PDF

    Description

    Explore the key factors and characteristics of Alzheimer's disease, the most common form of dementia. This quiz delves into the progressive nature of AD, its pathological features, and the role of amyloid precursor protein (APP) in Aβ formation.

    More Like This

    Use Quizgecko on...
    Browser
    Open
    Browser
    Browser