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Understanding Alzheimer’s Disease: Mechanisms, Risk Factors, and Treatment

Dive into Alzheimer’s disease, exploring its progressive impact on memory, behavior, and cognition. Discover key risk factors, genetic components, and the intricate pathology involving amyloid plaques and neurofibrillary tangles. Explore potential treatments such as cholinesterase inhibitors and NMDA glutamate receptor antagonists.

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Understanding Alzheimer’s Disease: Mechanisms, Risk Factors, and Treatment

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  1. Neurotransmitters • Neuropeptides • Opioid peptides • Enkephalins (ENK) • Endorphins (END) • Peptide Hormones • Oxytocin (Oxy) • Substance P • Cholecystokinin (CCK) • Vasopressin (ADH) • Neuropeptide Y (NPY) • Brain-derived Neurotrophic factor • Hypothalamic Releasing Hormones • GnRH • TRH • CRH • Lipids • Anandamide • Gases • Nitric Oxide (NO) • Amines • Quaternary amines • Acetylcholine (ACh) • Monoamines • Catecholamines • Epinephrine (EPI) • Norepinephrine (NE) • Dopamine (DA) • Indoleamines • Serotonin (5-HT) • Melatonin • Amino acids • Gamma-aminobutyric acid (GABA) • Glutamate (GLU) • Glycine • Histamine (HIST)

  2. Acetylcholine Synthesis Breakdown

  3. Cholinergic Synapse • Choline • Acetyl CoA • Cholinesterase (ChAT) • Acetylcholinesterase (AChE) • Choline transporter • Vesicular ACh transporter (VAChT)

  4. Myasthenia Gravis

  5. Botulinum Toxin

  6. Autonomic Nervous System

  7. Figure 7.6 Anatomy of cholinergic pathways in the brain

  8. Cholinergic (Ach) System

  9. Nicotinic receptors • Muscle Type • Neuromuscular junction • Autonomic ganglia • CNS Type • Muscarinic receptors • M1 • CNS • Autonomic ganglia • M2 • Heart • M3 • Blood vessels • Lungs • Exocrine Glands • M4 • CNS • M5 • CNS Cholinergic Receptors Iontotropic metabotropic Nicotinic ACh Receptor

  10. Structure of the nicotinic ACh receptor

  11. Three common types of nicotinic ACh receptors

  12. Insulin Release

  13. Attentional Processing

  14. Morphine Reward

  15. Deadly nightshade (Atropa belladonna)

  16. Alzheimer’s Disease Chronic Progressive Dementia disorder Cases are expected to increase

  17. Projected rates of Alzheimer’s disease

  18. Disease Progression mild cognitive impairment (MCI) general forgetfulness progressive loss of memory issues with emotional behavior, personality, language, perception, thinking, and judgment anhedonia ability to name familiar objects or people is impaired problems with misplacing items or getting lost on familiar routes increase in frequency physiological problems such as disrupted sleep, incontinence, and difficulty swallowing psychiatric symptoms such as delusions, hallucinations, depressed mood, and agitation (including violent outbursts) may occur. communication skills are diminished loss of personal episodic memories leads to withdrawal from social contact Loss of the ability to use language, interact, and recognize loved ones

  19. Risk Factors Advancing Age Family History Obesity Untreated Hypertension High Cholesterol Stress Sedentary Lifestyle Head Trauma Hypoxic Brain Injury Depression Bipolar Disorder PTSD

  20. Alzheimer's: Biology • chromosomes 1, 14, 19, and 21 • general brain atrophy • neuronal degeneration • decreased cerebral metabolism • general decay of acetylcholine system • especially in the basal forebrain • neurofibrillary tangles • beta-amyloid plaques

  21. General Brain Atrophy

  22. General Brain Atrophy

  23. Neuronal Degeneration Normal Alzheimer’s

  24. Decreased Cerebral Metabolism Alzheimer's Normal

  25. Beta-Amyloid Plaques Beta-Amyloid Plaques Tau Filaments Pathology: • Interferes with Ca2+ regulation • Increases free radicals • Stimulates microglia aggregation • Increases inflammation

  26. Beta-Amyloid Plaque Formation Key enzymes: • Alpha-secretase • Beta-secretase • Gamma-secretase Beta-Amyloid Precursor Protein (BAPP) is cut or cleaved by these enzymes three different protein fragments form Protein fragments: p3 alpha and gamma harmless 40 amino acid string beta and gamma harmless 42 amino acid string beta and gamma TOXIC

  27. Visualization of Amyloid Plaques

  28. Neurofibrillary Tangles

  29. Neurofibrillary Tangles Microtubules: • Provide structural support • Are pathways for: • Nutrients • Waste products • Neurotransmitters Made of Tubulin In Alzheimer’s Disease: Excess Tau protein binds builds up Tau binds with Tubulin and tangles the microtubules preventing them from properly functioning

  30. Treatment • Cholinesterase inhibitors: improve cognition by increasing acetylcholine in the synapse by reducing its breakdown. • NMDA glutamate receptor antagonist memantine (Namenda): prevents the drastic increase in cell firing that leads to excitotoxicity, without significant side effects.

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