Alzheimer’s Disease (AD) is a neurodegenerative disorder that is characterized by progressive cognitive degeneration and eventual deterioration in diverse aspects of daily life. AD is typically associated with a decline in memory function, leading to a patient's inability to recall even their own loved ones or family. AD patients also show a decline in motor skills as well as changes in behavior and personality.
AD was first characterized by the German physician Alois Alzheimer. For several years he studied a patient suffering from dementia and memory loss; after her death he stained the tissues of her brain to look for abnormalities, and noticed a multitude of plaques and 'tangles', as well as an overall decrease in brain volume. Further study has revealed that the prevalence of these plaques is associated with the severity of symptoms in almost all AD patients, and also that they tend to proliferate with age. The plaques can actually accumulate outside of the neurons, and consist mainly of a single entity: β-amyloid (Aß), a subunit of the protein called β-amyloid precursor protein (APP). Since this discovery, investigation has focused on β-amyloid, to determine whether the accumulation of this protein somehow causes the psychological symptoms of AD, or whether instead it is simply a symptom of another process.
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 alteration in the expression or processing of the amyloid precursor protein (APP), which leads to an accumulation of beta-amyloid. The gradual accumulation of Aß initiates a complex, multistep cascade that includes gliosis, inflammatory changes, synaptic changes, tangles and transmitter loss (1). This theory has gained considerable credibility in recent years, but a detailed picture of how Aß accumulation leads to such profound effects remains unclear.
The Amyloid Cascade Hypothesis
Picture source: http://www.alzforum.org/res/adh/cur/knowntheamyloidcascade.asp
α β γ
The generation of Aß from APP is complex, as the APP protein is cleaved several times in the cell. APP is a membrane-bound protein, with a small intracellular domain and a large extracellular domain; it is hypothesized that the extracellular domain mediates cell-cell signalling, while the intracellular domain relays those signals to the rest of the cell. APP is normally cleaved by three secretase genes, called α β or γ-secretase. One form of cleavage generates small peptide products that do not form amyloid plaques or tangles; these are mediated by α- and γ-secretase. However, the activity of β-secretase in conjunction with γ-secretase generates a small product that can form the amyloid plaque: this is β-amyloid itself.
Changes in the activity of the secretase proteins can favor non-pathogenic or pathenogenic products; if α-secretase activity decreases, or β-secretase activity increases, more β-amyloid will be formed. As expected, several mutations have been found in human AD patients that affect secretase activity. In addition, mutations in APP itself can favor the generation of the 42-aa product, which is more pathenogenic than the 40-aa product. Interestingly, α,γ cleavage appears to occur extracellularly, while β,γ cleavage occurs entirely in the endosomal-lysosomal compartment.
Processing of the APP Protein
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).
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.
The Morris water maze is used as a common behavioral test for mice and rats to determine their spatial memory ability. This test was first developed in 1984 by neuroscientist Richard G. Morris, and involves placing the rat in a filled basin of water and measuring the ability of the rat to find floating platforms to stand on. There are two common types of Morris water mazes: ones involving visible platforms, and ones involving “invisible” or clear platforms. The former is used to test visual and motor sense, while the later is used to test the animal’s memory. In order for the rat to find the platform in the case where invisible platforms are used, visual cues are usually placed outside the tank of water. If the same rat is used in multiple trials, it will be observed that the rat becomes more efficient in finding the invisible platform, presumably because it remembers where the platform was in previous trials. However, hippocampal lesions and NMDA receptor blockers decrease the efficiency with which these rats find the invisible platforms after multiple trials. Control rats usually initiate a search pattern in the quadrant that previously contained the floating platform. Rats which have hippocampal lesions or that have been treated with APV (a NMDAR blocker) do not initiate search patterns in the quadrant that contains the platform after multiple trials, and instead search the entire tank. Thus, the hippocampus and NMDA receptors alike are necessary for spatial learning. Also, since long-term potentiation also requires NMDA receptors, it is possible that spatial learning is dependent on LTP.
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.
Sites for anti-Aβ intervention are indicated. Scissorsindicate proteolyitic cleavages. "sAPPβ refers to the large secreted derivative generated by β-secretase cleavage of APP(2)"
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.
Recent work has revealed a number of interesting twists in the story of β-amyloid and τ-tangle accumulation and the development of AD.
The scope on which AD is studied is enormous, and neither the Baptist or Tauist hypotheses are fully satisfactory. One problem with both results is that synaptic loss is the best predictor of cognitive decline, yet this synaptic loss can outpace either β-amyloid or τ-tangle formation. An explanation for this result places either APP or β-amyloid close to the synaptic machinery itself. One possibility is that β-amyloid acts in axonal transport; a decline in the regulation of this crucial process would first be seen as synaptic loss, followed by axonal retraction, and could be very sensitive to perturbation. Evidence for this includes the controversial result that mutation of APP in the fruitfly, Drosophila melanogaster, causes defects in axonal transport that resemble mutations in the transport machinery itself. A related hypothesis suggests that a diffusable form of β-amyloid may cause neuronal toxicity without a requirement for plaque buildup, yet still act on the cell body itself.
An interaction between stress hormones and memory as well as basic cognition long been suspected. One of the early symptoms of AD is the breakdown of the hypothalamic–pituitary–adrenal axis (which regulates stress and sex hormones), and leads in particular to an increase in the stress hormone cortisol. Interestingly, though, the rise in cortisol is not just a symptom of AD; instead, increases in cortisol levels appear to increase β-amyloid formation by upregulating APP as well as the β-secretase. In addition, cortisol seems to induce τ-tangle accumulation. This provides a new avenue for AD therapy, in which modulation of glucocorticoid levels may slow the progress of the disease.
Catalano SM, Dodson EC, Henze DA, Joyce JG,Krafft GA, Kinney GG (2006). The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer's disease. Curr Top Med Chem. 2006;6(6):597-608.
Golde TE.(2003)Alzheimer disease therapy: can the amyloid cascade be halted? J Clin InvestJan;111(1):11-8
Green, K., M, B.L., Benno, R., et al. (2006). Glucocorticoids Increase Amyloid-beta and Tau Pathology in a Mouse Model of Alzheimer's Disease. J. Neurosci., 26(35), 9047-9056.
Hardy JA, Higgins GA.(1992)Alzheimer's disease: the amyloid cascade hypothesis.ScienceApr 10;256(5054):184-5.
Stokin, G.B., & Goldstein, L.S. (2006). Axonal transport and Alzheimer's Disease. Annual Review of Biochemistry, 75(1), 607-627.
Recent updates to the site: