Alzheimer’s Disease: Formation of amyloid peptides and plaques in vivo
Ben Zeskind and Stephanie Chang
Alzheimer’s Disease (AD) is a neurodegenerative disorder affecting more than 4 million Americans, particularly those
over the age of 65. Those afflicted with Alzheimer’s experience loss of short-term memory, dementia, and decreased mental
capacity. Its causes are genetic, behavioral, and environmental. Over the past 15 years, researchers have begun to develop an
understanding of the cellular and molecular mechanisms underlying the disease.
Alzheimer’s initial causative event is the cleavage of a
protein known as Amyloid Precursor Protein (APP) by - and
-secretase instead of the normal -secretase. This produces a
toxic A-42 peptide which forms insoluble extracellular
aggregates. In combination with other proteins, A-42 forms
plaques and long fibrils with cross-beta pleated sheet structure.
When A-42 interacts with metals such as Fe2+ and Cu+, oxidative
agents are created, which leads to damage of ion channels, cell
surface receptors, and other vital cellular components.
Damage to ion channels disrupts Ca2+ homeostasis,
causing extensive cellular damage which includes
hyperphosphorylation of tau, a microtubule protein. This
altered form of tau contributes to the degradation of the
cytoskeleton and to the formation of extracellular neurofibrillary
tangles (NFTs).
Image from Ingram Reference Below.
Experiments over the past two decades have demonstrated that healthy cells
produce soluble extracellular forms of A. Other research has established a
correlation between genetic predisposition to AD and increased levels of extracellular A-42. Further studies have shown that
elevated levels of dementia in patients are also connected with increased levels of extracellular A-42.
Genetic predisposition to AD can be a result of mutations in the APP sequence which increase the likelihood that
APP will be processed into A-42 instead of a more benign form. Mutations in other genes (such as PS1 and PS2) alter the
activity of -secretase.
Today’s therapeutic approaches to treating AD focus on several areas. Behavioral therapy includes low-fat, low
cholesterol, seafood-rich diets (cholesterol also predisposes individuals to AD for reasons that are not fully understood but may
involve altered membrane fluidity). Mental stimulation and an active lifestyle also reduce the risk of AD.
More aggressive therapies currently under development involve using exogenous antibodies to remove A-42 from
the brain, stimulating the body’s immune system to eliminate A-42, or blocking the action of -secretase. Less direct
therapies include chelators, which reduce the action of Fe2+ and Cu+, preventing oxidative damage, and statins, which lower
cholesterol. It is not yet clear that any of these therapies will cure Alzheimer’s, so significantly more research is needed.
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