Alzheimer's Disease Lecture Notes PDF

1 2  Alzheimer’s Disease Changes to the brain - significant decline of brain size (cellular loss) - large quantities of neurons stop functioning - lose connections with other neurons (disrupts neuronal communication), and die Frequently, neurons and thei...

1 2  Alzheimer’s Disease Changes to the brain - significant decline of brain size (cellular loss) - large quantities of neurons stop functioning - lose connections with other neurons (disrupts neuronal communication), and die Frequently, neurons and their connections in memory areas (entorhinal cortex and hippocampus) are impacted first Then progresses to cerebral cortex areas responsible for language, reasoning, and social behavior - damage is widespread Gradually lose ability to live and function independently Most current treatments focus on the symptoms: small improvements in cognitive function or delay cognitive decline - no current medication is able to stop or reverse the underling progress of this disease 3  Alzheimer’s Disease Form of dementia: most common - 10% of population above 65 - 50% older than 85 This is where most drug efforts Pathologically two very noticeable features have been focused on ~ last 15 - formation of β–amyloid (Aβ) plaques years: prevention or breakdown of - neurofibrillary tangles (hyperphosphorylation of the tau protein) these (mostly Aβ) 4  AD: Investigative Treatments in 2024 Phase 3 Clinical Trials Cummings et al., 2024 Most focus in on treatments that modify the disease (DMT = disease modifying therapies) - DMT account for the majority of treatments = 65% of phase 3 trials (in 2024) - other therapies focus on the symptoms (some growth in this approach in last 2 years) In 2024, there are 32 potential drugs being evaluated in phase 3 clinical trials, and another 81 in phase 2 5  Key Factors in Alzheimer’s Disease: Normal Enzymatic Degradation β–amyloid (Aβ) is a fragment of a larger protein - β-amyloid precursor protein (APP) is in neuronal membrane (implicated as a regulator of synapse formation) The APP is cleaved off/cut by different enzymes - first cut by (alpha) α-secretase (predominant, normal APP processing) to result in sAPPα peptide - followed by (gamma) -secretase cutting the protein that remains in the membrane to form P3 peptide - does not lead to plaque formation 6  Key Factors in Alzheimer’s Disease: Aβ Formation The APP is cleaved off/cut by different enzymes: - first cut with (beta) β-secretase (resulting in sAPPβ peptide) - followed by (gamma) -secretase cutting the protein that remains in the membrane to form Aβ - position of the -secretase cut determines if pathogenic or not - there are subtypes of Aβ (long and short = # of amino acids) but the Aβ42 (long) is considered the pathogenic one leading to amyloid plaque formation 7  Key Factors in Alzheimer’s Disease Aβ oligomers - collection of Aβ42 fragments (prior to plaque formation) - some take on an odd shape (misfolded) causing others to do the same – prion (acts like infectious agent) - misfolding facilitates aggregation leading to amyloid plaque formation Aβ42 8  Key Factors in Alzheimer’s Disease Aβ oligomers, fibrils, and amyloid plaques - can damage neuronal membrane - neurotoxic leading to synaptic loss/neuron death - also interferes with neuronal communication (disrupting ion channels, ion flow, receptors, and synaptic communication) 9  Failed Approaches for Pharmacological Treatment of AD Modulate the enzymes - Semagacestat inhibits  secretase (failed) - Tarenflurbil shift the cleavage site (failed) - Verubecestat, Atabecestat, and Lanabecestat β-secretase (BACE1) inhibitors (failed, may even worsen cognition) 10  Approaches for Pharmacological Treatment: Aβ Prevent Aβ42 aggregation (make less “sticky”) - bind to Aβ42, interfere with others binding and forming plaques (Tramiprosate – failed in phase 3) Clear out Aβ oligomers - prevents plaque formation - upregulate Aβ “transport proteins” (P-glycoprotein, LRP1) to remove from brain Immunize for Aβ42 or the plaques (use the immune system to attack Aβ42 or the plaques) 11 Recent News Aduhelm approved in June 2021 for patients with mild cognitive impairment or mild dementia stage of disease - a monoclonal antibody that binds to aggregated forms (not the monomers) or amyloid plaques - believed to clear from brain and/or lead to glial cells digestion of amyloid Controversy: drug did not show efficacy above the placebo group - has been shown to remove plaques, but clinical improvement still not that apparent - approved based on the reduction of plaques - FDA academic advisors voted: 10 against approval, 1 uncertain - several FDA advisors resigned - also: MRI abnormalities found in 41% of patients = may be swelling/bleeding in brain 12 Recent News Drug discontinued in 2024 13 14 BREAKING NEWS Leqembi (lecanemab) approved in May 2022 for patients with mild cognitive impairment or mild dementia stage of disease - a monoclonal antibody interferes with the formation of Aβ fibrils Kisunla (donanemab) approved in July 2024 - a monoclonal antibody that works similarly to Aduhelm but may clear more plaques Need for patients to take these drugs as early as possible in disease - if plaques cleared, may come off drugs until new plaques are observed - significant side effects still include swelling/bleeding in brain 15  Key Factors in Alzheimer’s Disease Apolipoprotein E (ApoE) Potential treatment - produced by microglia - neutralize with an antibody - most significant genetic risk factor for AD so far - degrade or transport it out identified = ApoE4 gene - stabilizes Aβ oligomers - impairs degradation - enhance activity of -secretase 16  Key Factors in Alzheimer’s Disease Tau proteins - stabilize microtubules and aid the assembly of tubulin in the microtubules - become hyperphosphorylated (add phosphate groups) in AD = disrupt its normal function 17  Key Factors in Alzheimer’s Disease Tau proteins - without tau to stabilize the microtubules, their transport function is disrupted (synaptic vesicles) - develop neurofibrillary tangles (accumulation of tau proteins) inside of the neuron - disrupts neuron function and can lead to neuronal death 18  Approaches for Pharmacological Treatment: Tau Prevent Tau aggregation or phosphorlyation - AADvac1 & 2, Semorinemab, LMTM (failed), and ABBV-8E12 (failed): vaccine/molecule/antibody that prevent tau aggregation and/or increase clearance (some in Phase 2 and 3) - kinase inhibitors to prevent phosphorylation (preclinical) 19 “Ya, I know that” Quiz... Which enzyme starts the process leading pathological amyloid plaque formation? A 20 “Ya, I know that” Quiz... Which enzyme starts the process leading pathological amyloid plaque formation? Answer D: β-Secretase 21  Alzheimer’s Disease (Transmitters) ACh - ACh is an important transmitter in learning and memory (hippocampus and other sites) - one of first systems to be affected in AD - low levels of ACh are found in AD due to excessive degradation by acetylcholinesterase (AChE) - = impaired memory 22  Alzheimer’s Disease (Transmitters) Glutamate - excessive glutamate in synapses due to dysfunction of reuptake protein and degradation enzymes (both may be caused by β amyloid) - this causes over-activation of NMDA receptors allowing high influx of Ca2+, which is cytotoxic and leads to neuronal death 23  Approaches for Pharmacological Treatment: NT’s Fix neurotransmitter problems: Slightly efficacious in some people, perhaps slowing the disease - inhibit AChE to increase ACh (donepezil, galantamine) progression and improving memory (temporarily) - block NMDA channel to limit Ca2+ influx (memantine) - affects symptoms and not the disease NMDA channel AChE 24 Take home… Alzheimer’s disease is a progressive disorder that is the result of neuronal dysfunction/death due to different pathological aggregations, atypical inflammation, and neurotransmitter abnormalities as well as an association with other age-related ailments Current treatments have minor and temporary effects on symptoms as therapies directed at disease modification have seen limited success to date in recent clinical trials: but disease modification is the major focus in current clinical trials and recently approved drugs - are the patients being treated too late??? (need to identify and treat disease prior to plaques and tangles) 25  Guess the “recreational” drug… intense energy/alertness analgesia Opioids euphoria Cannabis/THC euphoria euphoria disinhibition sensitive to touch, sound, light relaxed relaxed intense happiness drowsiness and mental clouding slow cognitive function/lack of focus irritable Cocaine mild respiratory depression enhanced perceptions/warmth paranoid delusions and hallucinations increased appetite decrease appetite Amphetamine pain reduction aggression Alcohol psychosis (some users) heightened sexual interest Opioids depersonalization/agitation/paranoia MDMA (also in some users) Cannabis/THC Cocaine euphoria euphoria increased self-confidence hyperactive anxiolytic Alcohol sense of well-being alert Amphetamine sedation increased sociability/empathy motivated impairs motor coordination reduced anxiety euphoric including slurring of speech enhanced emotionality sustained physical efforts without sleep disrupts REM sleep mild hallucinations MDMA enhanced athletic performance lack of inhibition enhanced sensations psychosis impaired judgement enhanced sexuality weight loss (decreased appetite) aggression altered sense of time motor 26 memory impairment analgesia  Opioids Opioids - H, Hammer, Skag, Gear, Smack , Horse, Nose drops, China white, White, White dynamite, Dragon - G-coupled (metabotropic) receptors - Mu (µ1 and µ2), delta (δ), kappa (κ), opioid-like/nociceptin/orphanin FQ/sigma (σ, OFQ, NOP-R ) β-endorphin enkephalin dynorphin nociceptin Ligands/peptides endomorphin Morphine - most ligands bind to multiple opioid receptors (different affinities/potencies) except NOP-R - origins from 4 propeptides: pro-opiomelanocrtin (POMC), proenkephalin, prodynorphin, pronociceptin 27  Opioids Opioids - generally inhibitory - presynaptic Morphine presynaptically inhibits GABA release (heteroreceptor) in VTA - GABA is an inhibitory transmitter (can inhibit dopamine release) - by inhibiting GABA, morphine removes a “brake” on dopamine (DA) release in the NAc via mesolimbic pathway - results in increased dopamine (DA) levels in NAc 28 Opioids - found all over nervous system (µ, δ), but heavy concentration in sites of reward and pain 29  Psychomotor Stimulants Cocaine Amphetamine - coke, snow, blow, rock , crack , candy, powder, dust, big C, rocks, - speed, crystal, ice, uppers, Bennies, black or blue mollies, meth, base… crank , zip, eye openers, go… - L- and D-amphetamine, methamphetamine (synthetic) - cathinone, ephedrine: plant based - increases DA, 5-HT, and NE - increases DA, 5-HT, and NE 30  Stimulant Behaviors by Transmitter Dopamine Norepinephrine Serotonin Euphoria Anxiety Agitation or restlessness Addictive properties Aggression Confusion Hallucinations Irritability Rapid heart rate and high blood pressure Paranoia Mania Dilated pupils Impulsive behavior Hypertension Loss of muscle coordination or twitching musc Difficult breathing Stress Muscle rigidity Insomnia Heavy sweating Hyperactivity Diarrhea Headache Shivering Goose bumps Mesolimbic Locus coeruleus to: Brainstem (raphe nuclei) to: Mesocortical - forebrain - forebrain Nigrostriatal - cerebellum - spinal cord - spinal cord 31  Psychomotor Stimulants Mechanism Cocaine Amphetamine - increases DA, 5-HT, and NE - increases DA, 5-HT, and NE - binds and inhibits their transporters - inhibits transporters, inhibits degradation (MAO), and induc release (reverse transporters) = massive increase Cocaine & Amphetamine stop DA, NE, 5-HT uptake by transporters - thus, more DA, NE, 5-HT remains in cleft X Amphetamine X MAO inhibits degradation by MAO Amphetamine - thus, more DA, NE, and 5-HT available for DA flows out through transmission transporters (reverse transportation) - thus, brings more DA into synaptic cleft 32  Methylenedioxymethamphentamine (MDMA) MDMA - ecstasy, moly, X, XTC, Beans, Adams, clarity, hug, love drug - a derivative of amphetamine - increases DA, 5-HT, and NE through inhibition of transporters - stronger influence on 5-HT transporters - MDMA decreases activity in amygdala (better cognitive control of emotions) - increased activity of the amygdala normally associated with negative affect (emotion) - results in reduced fear/anxiety 33  Cannabis ∆9-Tetrahydrocannabinol (THC) - pot, herb, Mary Jane, holy weed, happy cigarette, gunga, kush, bud, grass, lobo, meg, righteous bush, maui-wowie….(more than 100 names) - CB1 and CB2 receptors (metabotropic) - CB2: mostly on non-neuronal cells, e.g., immune cells (low levels on CNS neurons) - endogenous lipids are agonists (endocannabinoids): anandamide, 2-arachidonoylglycerol (2-AG) 34  Cannabis ∆9-Tetrahydrocannabinol (THC) - CB1: mainly presynaptic heteroreceptors – inhibitory - inhibits ACh, 5-HT, GABA, glutamate - endocannabinoids (lipids) have retrograde (release by post-synaptic neuron), non-retrograde, and neuron-astrocyte signaling presynaptic postsynaptic eCB = endocannabinoid 35  Cannabis CB1 expressed in many CNS sites - diverse effects when activated - receptors in VTA can indirectly both increase (via GABA inhibition) and decrease (via glutamate inhibition) DA release in the NAc - if the inhibition is more predominant on GABA neurons, then the net effect is to increase DA (to produce reward) MUNCHIES? - causes release of hormone ghrelin from stomach to stimulate hunger - inhibits satiety in hypothalamus - diminishes olfactory habituation (increases sensitivity to food smells and decreases satiety) 36  Alcohol Alcohol – Ethyl alcohol (ethanol) - juice, sauce, hooch, vino, liquid courage, booze, firewater, hooch, sauce, spirit, poison, giggle juice - difficult to determine mechanism of action (widespread and effects most transmitters and systems) Alcohol: Enhances GABA Actions - positive allosteric modulation (PAM) of GABA A receptors - results in increased inhibition (Cl- influx) of neuron 38 Alcohol: Decreases Glutamate Related Excitation - reduces glutamate release by pre-synaptic action (increases activity at mGluR autoreceptors) - inhibits post-synaptic ionotropic glutamate receptors (AMPA and NMDA) - results in less glutamate activity (less excitation) 39  Alcohol: Enhances Opioid System - Enhances β-endorphin release - results in increased DA in NAc (similar to morphine effect) Alcohol increases β-endorphin release in the VTA to inhibit GABA neurons - GABA in an inhibitory transmitter - by inhibiting GABA, β-endorphin removes a “brake” on dopamine (DA) release in the NAc via mesolimbic pathway - results in increased dopamine levels in NAc 40 Alcohol: Messes with Neuronal Structure/Function interferes with neuronal lipid membranes - membrane deformation interferes with 2nd messenger systems - stimulates G-proteins 41 42  Which drug has a strong association with decreasing aversive activity in the amygdala? Answer A: MDMA 43  Take home… Elevating dopamine content and activation of the reward circuits are important characteristics of most recreational drugs However, each drug brings it own elements that are dopamine independent to produce its effect - but the mechanisms for several of these drugs are not totally worked out 44  To do for next week Read Journal Club paper: Beau + Jackson + Emily + Adrienne: “Icariin alleviates autistic-like behavior, hippocampal inflammation and vGlut1 expression in adult BTBR mice” by Jiang et al., 2023 Expectations for “Treat a Neurological Disease” Review for exam - go over format of exam - come with questions if there are topics you would like to review 45 Final Thoughts… 46