BIO254:Amyloid

Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disorder symptomatically characterized by progressive cognitive degeneration and eventual deterioration in diverse aspects of daily life, including motor skills, behavior, and personality. One of the primary pathological features that characterizes Alzheimer’s disease is the deposition of extracellular ß-amyloid plaques in the brain. These extracellular plaques contain many components such as axon terminals, microglia, astrocytes, and aluminum. The major constituents of the plaques are ß-amyloid peptides (Aß), in two main types: 40 amino acids and 42 amino acid sequences. Aß is a 4 kiloDalton peptide that aggregates to form the least soluble, fibrillar component of AD amyloid plaques. Aßs are liberated from a transmembrane amyloid precursor protein (APP) via cleavage by ß and γ secretases. Alternatively, cleavage of APP by α secretase occurs within the Aß region, preventing the release of an intact Aß peptide. Approximately 10% of AD cases are familial and arise primarily from autosomal dominant mutations in APP, presenilin I, or presenilin II. These presenilins are essential components of γ-secretase.

The Amyloid Hypothesis

It is currently unclear whether amyloid plaques are the primary cause of Alzheimer's disease (AD) or the result of it, although studies of APP fragments not found in AD patients are under way. Amyloid also seems to be deposited in the exterior of neurons in several unrelated disorders.

Amyloid plaques consist mainly of beta-amyloid protein, but additional protein components such as apoE are also present. Normally, soluble beta-amyloid protein is metabolized, but in AD, it is formed inside the neuron via cleavage of APP and is then deposited outside the cell. Unfortunately, it is unclear how polymerization of the normally soluble protein is converted into an insoluble aggregate.

Neuropathologic studies investigating the pathogenic role of amyloid in AD are still inconclusive. Some quantitative immunoassays reveal that equal amounts of soluble APP are found in the brains of AD patients and age-matched individuals with no AD symptoms. These results cast doubt on the role of APP. In fact, dense plaques accumulate with age, even in people who have no cognitive impairment.

On the other hand, the strongest evidence of amyloid playing a key role in the onset of AD may be found in the genetic studies of families with APP mutations. However, the correlation between APP mutatuions and AD does not imply that APP causes the disorder, since relatively few families are found with this genetic mutation.

Additional genetic evidence for the role of amyloid in AD is found in patients with Down syndrome (trisomy 21). In this case, significant amyloid accumulation is observed and is sufficient to cause similar neuropathologies also found in AD.