Alzheimer’s Disease Therapeutic Strategies

Alzheimer’s Disease Therapeutic Strategies

• Therapeutic strategies in Alzheimer's disease require recognition of the many factors influencing its development and risk factors.
• Altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of Ab is a key factor.
• The Ab cascade hypothesis and UPR are pathways associated with Alzheimer's disease development.
• Insulin in the brain: Alzheimer’s as diabetes type III indicates the potential link between diabetes and Alzheimer's disease.
• Impaired glucose metabolism in Alzheimer's disease is a common characteristic.
• Ab and oxidative stress are linked factors in Alzheimer's disease pathology.
• Perturbed calcium homeostasis and excitotoxicity are critical mechanisms contributing to the disease.
• Inflammation in Alzheimer's disease contributes to its progression.
• Risk factors include ApoE4 genotype and maternal transmission.

Anti-Ab Monoclonal Antibodies

• LECANEMAB (Esai’s and Biogen’s) is an FDA-approved anti-Ab monoclonal antibody that slows cognitive and functional decline by 27%.
• LECANEMAB is recommended for patients with Mild Cognitive Impairment (MCI) and mild Alzheimer’s disease, particularly those who are ApoE4 positive, but not for moderate or severe cases.
• ADUCANUMAB (ADUHELM) (Biogen) is another anti-Ab monoclonal antibody with potential slowing of cognitive decline, but the effectiveness is disputed.
• DONANEMAB (Lily) is another anti-Ab monoclonal antibody, potentially slowing cognitive decline by 35%.

Glutamatergic Inhibitors

• The glutamate pathway focuses on the role of sustained NMDA receptor activation leading to excessive Ca2+ influx (excitotoxicity), neuronal dysfunction, and cell death.
• Memantine hydrochloride (Namenda, Namzaric) is a low-affinity NDMA receptor antagonist used to treat moderate to severe Alzheimer's disease.
• NMDA receptors are composed of different subunits, NR1 and NR2A-D, responsible for binding sites for glycine (co-agonist) and glutamate (agonist).
• NMDA receptor opening occurs when glutamate and glycine bind, and the Mg2+ block is removed, allowing Ca2+ and Na+ influx.
• S-nitrosylation of cysteine protein in the receptor can reduce channel activity and is associated with the stimulation of the NMDA receptor.
• Excessive release of glutamate or overstimulation of the NMDA receptor can lead to excitotoxic cell death.
• Ca2+ influx following NMDA receptor activation triggers various processes that can lead to apoptosis, including activation of the p38 MAPK pathway and nNOS, resulting in NO formation and toxic effects.

Cholinergic Enhancers

• Donepezil (Aricept) is a cholinesterase inhibitor that increases acetylcholine levels in the brain.

GLP-1 Agonists

• GLP-1 receptor agonists (liraglutide) have been found to be neuroprotective in mouse models of Alzheimer's disease.
• Insulin signaling is impaired in Alzheimer's disease patients, making it a potential target for treatment.

Nasal Insulin

• Nasal insulin administration is a potential treatment strategy for Alzheimer's disease, with clinical trials underway to assess its effectiveness.

Explore the therapeutic strategies for Alzheimer's disease, focusing on the underlying mechanisms and risk factors. This quiz covers altered proteolytic processing, the Amyloid cascade hypothesis, and the implications of brain insulin and glucose metabolism in the disease. Learn about the pivotal roles of oxidative stress, inflammation, and genetic factors like ApoE4 in Alzheimer's progression.