Alzheimer's Disease Mechanisms Overview

Overview of Alzheimer's Mechanisms

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain.
• These abnormal protein aggregates disrupt neuronal communication and lead to neuronal death, resulting in cognitive decline, memory loss, and behavioral changes.

Amyloid Plaques

• Amyloid plaques are extracellular deposits primarily composed of beta-amyloid (Aβ) peptides.
• Aβ peptides are generated from the amyloid precursor protein (APP) through sequential enzymatic cleavage by β-secretase and γ-secretase.
• The accumulation of Aβ peptides disrupts neuronal function and promotes inflammation, contributing to neuronal damage.
• Mutations in APP, presenilin 1 (PS1), and presenilin 2 (PS2) genes are associated with familial forms of Alzheimer's disease, often resulting in increased production of Aβ peptides.

Neurofibrillary Tangles

• Neurofibrillary tangles are intracellular aggregates of hyperphosphorylated tau protein.
• Tau protein normally stabilizes microtubules within neurons.
• Hyperphosphorylation of tau disrupts its normal function, causing it to detach from microtubules and aggregate into tangles.
• These tangles interfere with axonal transport and neuronal communication, further contributing to neuronal dysfunction.
• Mutations in the tau gene (MAPT) can cause familial forms of AD and are linked to earlier onset and more severe disease progression.

Genetic Predisposition

• Familial AD cases account for a small proportion of total cases.
• However, genetic factors play a role in sporadic AD as well, influencing susceptibility.
• Genes such as APOE, and additional genes are implicated in the risk of developing AD through various mechanisms.
• Variations in these genes influence Aβ metabolism, tau phosphorylation, and neuron resilience.

Other implicated factors in Alzheimer's Disease

• The role of oxidative stress and inflammation in neuronal damage and AD progression is increasingly recognized.
• Oxidative stress can damage cell components, including proteins and lipids.
• Inflammatory responses contribute to neuroinflammation, which is a feature of AD, resulting in neurons dysfunction.
• Environmental factors like diet and lifestyle may further influence susceptibility to AD by affecting the risk factors already discussed.

Current Therapeutic Strategies

• Current therapies primarily focus on managing symptoms and slowing the disease progression, rather than curing it.
• Some drugs aim to reduce Aβ accumulation and aggregation.
• Other approaches target tau phosphorylation and aggregation.
• Research continues to explore novel therapeutic targets and strategies.