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.

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.

"Baptists" vs. "Tauists"

In addition to amyloid plaques, neurofibrillary tangles are another pathological hallmark of AD. Some AD researchers believe that these tangles along with tau, its major protein component, is more central to AD pathology than Aβ because the density of neurofibrillary tangles showed a better correlation to the severity of AD symptoms than did the level of Aβ deposition. Scientists who support the tangles/tau theory have since been dubbed “Tauists” while those who support the amyloid theory have been labeled “Baptists.”

Neurofibrillary tangles are insoluble aggregates that accumulate in degenerating neurons. Their main component is a cytoskeletal protein called tau. Tau normally binds to and regulates microtubule polymerization, but in AD tau proteins become hyperphosphorylated and aggregate, resulting in microtubule depolymerization along with the degeneration of a cell’s axons and dendrites. The so-called “tangle-tau” hypothesis suggests that this cascade of events ultimately leads to neuronal death in AD.

Numerous studies have looked at various correlations of tau and Aβ with AD pathology, but with mixed results. There seems to be a good correlation between cognitive performance and the level of tangles, but there also seems to be a good correlation between the cognitive decline and the levels of Aβ. One study looked at transgenic mice that overproduced both tau and APP (a “double mutant,” produced by crossing mice transgenic of tau with mice transgenic for APP), and compared their brains to those from the single mutants. The study showed that not only was the number of neurofibrillary tangles increased in the double mutant, but the tangles were also found in areas of the brain that were previously unaffected in the single tau mutant. The levels of Aβ deposits however, were similar between the double mutant and the single mutant. These results suggest that tangle and plaques are pathologically related, although it remains unclear if Aβ or APP plays a role in tangle formation or the other way around. Evidences that suggest Aβ playes a central role in the pathogeneisis of neuronal dysfunctional in AD includes the fact that Aβ is the subunit of the amyloid that is progressively deposited in myriad neuritic plaque in the limbic and association cortices of all AD patients. In addition, synthetic Aβ peptides are toxic to hippocampal and cortical neurons, both in culture and in vivo. Finally, the APP gene is on human chromosome 21q, and its duplication leads to the typical AD neuropathology that invariably develops in middle aged patients with trisomy 21 (down syndrome).

Memory Testing

A common behavioral test for mice and rats to determine memory ability or degeneration is the Morris water maze test memory. It looks to see if mice remember where a platform is in water to stand on. Visible platforms requires just visual and motor senses, not memory. Visible platforms are made hidden, where the rat needs to use cues outside the tank, to see if the mouse or rat returns to the visible platmorm's original spot to look for it.

Recommended reading: Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN. The role of beta amyloid in Alzheimer's disease: still a cause of everything or the only one who got caught? Pharmacol Res. 2004 Oct;50(4):397-409.

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. The blood brain barrier blocks antibodies, but there is a equilibrium with A-beta monomers and plugs. Monomers can pass through blood brain barrier so that drives equilibrium to reduce the amount of aggregate in brain. It showed some improvement in plaque accumulation and behavior in mice trials. 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.

References

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