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. In 1992, Jonh Hardy and Gerald Higgis, proposed the Amyloid Cascade Hypothesis for AD (1). 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).
Amyloid Cascade Hypothesis Diagram
Picture source: http://www.alzforum.org/res/adh/cur/knowntheamyloidcascade.asp
APP processing
Processing of APP can occur via two pathways. One involves cleavage within Aß by the secretase, which generates peptide products that do not precipitate to form amyloid. The second pathway involves cleavage in the endosomal-lysosomal compartment,resulting in intact Aß that precipitates to form amyloid(1). See the diagram below for more details.
Picture Source:http://www.bmb.leeds.ac.uk/staff/nmh/amy.html
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.
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.
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.
