Alzheimer's Disease Mechanisms

Study Notes

Alzheimer's Mechanism

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaques and neurofibrillary tangles.
These plaques, primarily composed of amyloid-beta (Aβ) peptides, aggregate extracellularly disrupting neuronal communication and function.
Neurofibrillary tangles result from hyperphosphorylation of tau proteins, leading to their aggregation within neurons and disrupting intracellular transport.
The exact mechanisms linking Aβ, tau, and neuronal dysfunction are still under investigation.

Aβ Formation and Aggregation

Amyloid precursor protein (APP) is a transmembrane protein.
APP is cleaved by enzymes, including β- and γ-secretases, to produce Aβ peptides.
Aβ peptides are prone to aggregation, forming oligomers, fibrils, and plaques.
The formation of toxic Aβ oligomers may precede deposition of amyloid plaques.
Genetic variations in APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes increase the risk of AD, likely by influencing Aβ production or aggregation.
Impaired clearance of Aβ contributes to plaque formation in AD.

Tau Protein and Neurofibrillary Tangles

Tau is a microtubule-associated protein found in neurons, crucial for axonal transport.
Hyperphosphorylation of tau disrupts its normal function, leading to the formation of insoluble neurofibrillary tangles.
These tangles are found inside neurons in AD brains.
Genetic mutations and enhanced phosphorylation lead to tau pathology, contributing to progressive neurodegeneration.

Mutations and Genetic Predisposition

Specific mutations in APP, PSEN1, and PSEN2 increase the risk of early-onset familial AD.
These mutations increase the production of Aβ peptides, particularly those prone to aggregation.
APOE gene variants: the APOE ε4 allele is the strongest genetic risk factor for late-onset AD.
The APOE ε4 allele may influence Aβ clearance mechanisms or accelerate tau hyperphosphorylation.

Brain Aging and AD Risk

Age is the primary risk factor for AD.
Brain aging is associated with changes in neuronal structure, synaptic plasticity, and neuroinflammation, potentially making neurons sensitive to toxic impacts of Aβ and tau.

Underlying Mechanisms of AD

Inflammatory processes and glial activation play a critical role in AD progression.
Oxidative stress from free radicals can damage neurons and contribute to Aβ aggregation.
Impaired neuronal function and synaptic dysfunction occur early in the disease process and affect various brain areas, leading to cognitive impairment.
Neurotransmission dysregulation, primarily involving cholinergic systems, is a significant feature in AD.

Clinical Features of AD

Progressive decline in memory, thinking, and behavior.
Difficulties with language, problem-solving, and performing daily tasks.
Changes in personality and behavior.

Description

This quiz explores the underlying mechanisms of Alzheimer's disease, focusing on amyloid plaques and neurofibrillary tangles. Understand the role of amyloid-beta peptides and tau proteins in neuronal dysfunction and the genetic factors that influence these processes. Test your knowledge on the current understanding of Alzheimer's pathophysiology.