L3 - Alzheimers

Overview of Alzheimer's Disease

• Neurodegenerative disease that leads to dementia

• Influences memory retention and cognitive function

• Chapters in Rang and Dale provide comprehensive coverage.

Learning Outcomes

• Pathophysiology Understanding: Learn and practice explaining the disease's mechanism both scientifically and in lay terms.

• Molecular Basis: Understand the neurodegenerative processes and how they relate to Alzheimer's disease.

• Drug Mechanisms: Focus on acetylcholinesterase inhibitors and NMDA receptor antagonists, their side effects, and how they function.

• Emerging Treatments: Overview of newer therapies and mechanisms of action.

Pathophysiology of Alzheimer's Disease

• Alzheimer's characterized by:

  • Neurodegeneration

  • Synaptic loss

  • Accumulation of amyloid beta and tau proteins.

• Key Pathological Features:

  • Accumulation of beta-amyloid plaques and tau neurofibrillary tangles.

  • Misfolding and aggregation leading to cellular toxicity and inflammation.

Cholinergic System & Alzheimer's

• Deficits in cholinergic transmission leading to loss of cholinergic neurons particularly in the basal forebrain.

• Cholinergic neurons critical for memory and cognitive functions.

Pharmacological Approach

• Drugs target neurotransmission via: regulating release, modulating reuptake, and interacting with receptors.

• Primary Drugs Used:

  • Acetylcholinesterase Inhibitors: Eg. Donepezil, Rivastigmine, Galantamine.

    • Mechanism: Prevent breakdown of acetylcholine, enhancing neurotransmission.

    • Side Effects: Nausea, diarrhea, insomnia, muscle cramps.

  • NMDA Receptor Antagonists: Eg. Memantine.

    • Mechanism: Modulates glutamatergic activity, reducing excitotoxicity.

    • Side Effects: Dizziness, agitation, insomnia.

Neurotransmission & Drug Action Sites

• Four Main Drug Targets:

  • Receptors: Fast-acting (ligand-gated) and slow-acting (G protein coupled).

  • Ion Channels: Affect neuronal excitability (targeted by anticonvulsants).

  • Enzymes: Regulate neurotransmitter availability (e.g., acetylcholinesterase).

  • Transporters: Control reuptake of neurotransmitters from synaptic clef.

Barriers to Drug Delivery

• Blood-Brain Barrier (BBB): Specially regulates substance entry, a challenge for drug delivery.

  • Drugs must be lipophilic (fat-soluble) and small (below 400-500 daltons).

  • Focus on avoiding efflux transporters like P-glycoprotein.

Dementia and Alzheimer’s Statistics

• Dementia affects about 55 million worldwide, with projections to rise.

• In Australia, second leading cause of death; 500,000 currently, expected to reach 1 million by 2058.

• Alzheimer's is the most common dementia form.

Gross Anatomy Changes in Alzheimer's

• PET scans reveal reduced brain activity and smaller brain volume due to neurodegeneration.

• Reduced glucose metabolism and increased atrophy of brain structures critical for memory.

Protein Misfolding and Disease Progression

• Amyloid Beta Hypothesis: Accumulation leads to neurodegeneration and the loss of cholinergic neurons.

• Tau tangles contribute to transport failure in neurons.

• Both processes trigger inflammatory and excitotoxic responses.

Drug Development & Future Directions

• Current symptomatic treatments do not prevent disease progression.

• Research focuses on targeting amyloid plaques via monoclonal antibodies and tau-targeted therapies.

  • Challenges include balancing efficacy and safety.

Summary

• Current treatments: Shift towards disease-modifying therapies targeting underlying causes rather than symptoms. The need for effective treatments grows as the aging population increases.