L3 - Alzheimers

Pathophysiology Understanding: Explain the disease's mechanism scientifically and in lay terms.
Molecular Basis: Understand the neurodegenerative processes and their relation to Alzheimer's disease.
Drug Mechanisms: Focus on acetylcholinesterase inhibitors and NMDA receptor antagonists, including their mechanisms and side effects.
Emerging Treatments: Overview of newer therapies and their mechanisms of action.

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.

Deficits in cholinergic transmission lead to the loss of cholinergic neurons, particularly in the basal forebrain.
Cholinergic neurons are critical for memory and cognitive functions.

Drugs target neurotransmission by regulating release, modulating reuptake, and interacting with receptors.
Primary Drugs Used:
- Acetylcholinesterase Inhibitors: Eg. Donepezil, Rivastigmine, Galantamine.
- Mechanism: Prevent the breakdown of acetylcholine by inhibiting acetylcholinesterase, thereby increasing acetylcholine levels in the synaptic cleft and enhancing cholinergic neurotransmission. This helps compensate for the loss of cholinergic neurons.
- Side Effects: Nausea, diarrhea, insomnia, muscle cramps due to increased acetylcholine levels in the periphery.
- NMDA Receptor Antagonists: Eg. Memantine.
- Mechanism: Modulates glutamatergic activity by blocking NMDA receptors. This action reduces excitotoxicity caused by excessive glutamate stimulation, which can lead to neuronal damage. Memantine helps to stabilize neuronal function without completely blocking normal glutamatergic neurotransmission.
- Side Effects: Dizziness, agitation, insomnia.

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 the synaptic cleft.

Blood-Brain Barrier (BBB): Regulates substance entry, posing a challenge for drug delivery.
- Drugs must be lipophilic (fat-soluble) and small (below 400-500 daltons) to cross the BBB effectively.
- Focus on avoiding efflux transporters like P-glycoprotein, which can pump drugs out of the brain.

Dementia affects about 55 million people worldwide, with projections to rise.
In Australia, it is the second leading cause of death; there are currently 500,000 cases, expected to reach 1 million by 2058.
Alzheimer's is the most common form of dementia.

PET scans reveal reduced brain activity and smaller brain volume due to neurodegeneration.
Reduced glucose metabolism and increased atrophy of brain structures, especially those critical for memory, such as the hippocampus.

Amyloid Beta Hypothesis: Accumulation of amyloid beta leads to neurodegeneration and the loss of cholinergic neurons.
Tau tangles contribute to transport failure in neurons, disrupting axonal transport and leading to neuronal dysfunction.
Both processes trigger inflammatory and excitotoxic responses, exacerbating neuronal damage.

Current symptomatic treatments do not prevent disease progression.
Research focuses on targeting amyloid plaques via monoclonal antibodies and tau-targeted therapies to modify disease progression.
- Challenges include balancing efficacy and safety, as well as addressing the complexity of the disease.

Current treatments: There is a shift towards disease-modifying therapies targeting underlying causes rather than just