BIO254:Amyloid
History
The Amyloid Cascade Hypothesis was proposed in 1992 by Jonh Hardy and Gerald Higgis. This hypothesis suggested that the pathogenesis seen in Alzheimer’s disease patients is initiated by an altered expression or proteolytic processing of the amyloid precursor protein (APP) which leads to an accumulation of beta-amyloid (Aß), specifically Aß42. The gradual accumulation of Aß initiates a complex, multistep cascade that includes gliosis, inflammatory changes, synaptic changes, tangles and transmitter loss (1).
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.
According to current theories of the amyloid hypothesis, progressing stages of beta-amyloid aggregation disrupt neurons by clogging cell-to-cell communication, activating immune cells that trigger inflammation, and--eventually--killing neurons.
Treatments Against Amyloid Accumulation
Our continuing exploration of amyloid's role in Alzheimer's disease prompt us to question: If beta-amyloid does play a vital role in the onset of AD, then how could treatments block its affect? Currently, scientists are investigating several strategies to inhibit the effect of amyloid aggregation in memory loss. The most promising experimental strategies include:
Mobilizing the Immune System to Produce Antibodies to "Track" and "Attack" Beta-Amyloid
Neurobiologists have developed an experimental "vaccine" called AN-1792 that shows potential in animal trials. However, in human trials this drug caused serious brain inflammation and testing had to be stopped. Yet preliminary signs of the drug's effect have been shown: autopsies of patients taking the drug demonstrate that their brains contain fewer amyloid deposits than expected. One puzzling result of AN-1792 trials is that pateints who developed high levels of beta-amyloid antibodies also had increased brain shrinkage. Thus, another effective treatment may be to prevent or reduce brain shrinkage.
Administer Laboratory-Produced Antibodies to Beta-Amyloid
A safer method of administering "vaccines" is to use laboratory-produced antibodies instead of directly activating the immune system to produce its own. Lab-produced antibodies may be delivered in predetermined doses that do not persist in the human body after drug-intake stops. Several companies like Elan are developing laboratory-engineered anti-beta-amyloid antibodies.
Change How Proteins Cut APP into Beta-Amyloid
As mentioned above, secretases are proteins that are involved in cleaving APP into beta-amyloid. If we are able to change the catalytic behavior of secretases, we may be able to prevent or reduced beta-amyloid production. For example, secretase inhibitors block the cutting action of secretases. Additional approaches may reduce beta-amyloid concentrations by directing secretase to cleave APP into fragments other than beta-amyloid. Currently, the drug R-flurbiprofen (Flurizan) is a drug that may reduce beta-amyloid by targeting secretases.
Block Accumulation of Beta-Amyloid
Because amyloid accumulation results from an imbalance between protein fragment production and its clearance, blocking the aggregation or greatly reducing the clustering of beta-amyloid may help alleviate the effects of AD. Several beta-amyloid forms exist in the Alzheimer brain, but we do not currently know which form is the most toxic, but this knowledge would allow scientists to target a specific amyloid form. Drugs that prevent individual amyloid fragments from sticking together are called anti-aggregants.
