Alzheimer’s Disease: Antibodies to the Rescue?

Effective drug therapies have evaded researchers in hopes of overcoming Alzheimer’s disease (AD). The disease exhibits a complexity in its pathogenesis and progression, making it difficult to tackle the disease. With several hallmarks establishing AD, it offers researchers a variety of promising targets to understand and combat AD. Examples of promising targets would be inflammation, insulin resistance, neurofibrillary tangles, and beta-amyloid peptide fragments.

In our class discussion, we focused on how inflammation plays a role in AD. By the presence of inflammation, the immune system will recruit cytokines/chemokines that have shown to play roles in the neurodegeneration of AD. Discovering the role inflammation played in AD showed promising targets for drug therapies; however, the utilization of anti-inflammatories has not delivered the anticipated results in the arrest of AD progression, the restoration in cognitive function, or prevention.

The search in another area…

The beta-amyloid peptide that develops into plaques and oligomers is of great interest to researchers. The reasoning behind their interest is that when the parent amyloid protein is cleaved into the beta amyloid peptide fragments they become sticky allowing them to accumulate and cause plaques, which disrupts the neuronal network. The peptides also have the ability to stick to each other causing oligomers, which float into the synaptic space disrupting the ability for neurons to pass along information via signals. Both the plaques and synaptic disruption leads to necrosis of the neuron, which leads to brain shrinkage due to the lost of the neuronal network. The lost of the neuronal network produces the diminishing effects of brain function; as more of the network is lost, the severity of cognitive decline is exhibited.

Researchers hypothesize that beta-amyloid peptide is a major player in the development of AD. Targeting the beta-amyloid sticky fragments is plausible approach in developing effective drug therapies for AD. There are several strategies in approaching the problematic beta-amyloid peptide: blocking enzymes that produced the beta amyloid fragment, blocking aggregation of beta-amyloid into plaques, and the removal of the beta-amyloid fragments. Each of the strategies all target to result in the reduction of levels to inhibit plaque and oligomer formations.

What role can antibodies play?

Researchers believe they have found that by proper clearance of excess beta-amyloid peptide can halt the progression of AD and restore cognitive function. A way they attempt to accomplish this clearance is by employing the individual’s immune system. There is a nasal vaccine that uses active immunization by delivering a synthetic version of the beta-amyloid peptide with a carrier protein to induce an immune response. By building this response, the hope is for the individual’s immune system to successfully clear the beta-amyloid peptides before they become problematic by using anti beta-amyloid protein antibodies. The antibodies are suspected to be effective in clearing plaques after formation or preventing formation, giving the use of the vaccine a broad spectrum to be utilized in different stages of AD. There has been attempt (name of vaccine is AN1792) in 2002 to use this immunotherapy vaccine, but was terminated in phase 2 trials due to the development of meningoencephalitis and leukoencephalopathy in a small percentage of patients. However, the results from the clinical trials did indicate the vaccine was successful in the attempt to clear amyloid beta plaques. Due to those results, there is currently a second attempt (name of vaccine is ACC-001) with the same approach; however, to avoid the adverse effects from the first attempt; a modification was made by reducing the size of the synthetic beta-amyloid peptide that accompanies the carrier protein to induce an immune response; this vaccine is currently in phase 2 trials. Another way to induce antibody activity is instead of stimulating the individual’s immune system to develop antibody defense is to utilize passive immunization; the patient is delivered a vaccine that already contains the antibody (vaccine named is AAB-001), which this method may be more preferable due to the ability to regulate dosing of antibodies. It is currently in trials and showing great promise of reducing beta-amyloid plaques and restoring cognitive function. One last approach to mention in immunotherapies for AD is the use of intravenous immunoglobulin (IVIg) to reduce beta-amyloid levels, which has shown to be effective in the reduction of plaques and restoration of cognitive function; however, I question the practicality of this method. The IVIg is a collection of Ig antibodies from a pool of human donors- the pool consists of plasma from a large population of human blood donors. The availability and cost of IVIg are going to create obstacles in utilizing this immunotherapy in AD. Considering the growing rate of people being diagnoses with AD, makes it unlikely to be a source of future therapies also since it is a limiting resource, which not to mention this type of immunotherapy should first be available to individuals who lack or have impaired immune systems. In my opinion, this approach won’t be as reliable as the previous mention immunotherapies.

Are antibodies enough?

Though we have witness through mice models the reduction in beta-amyloid levels leads to reversing the cognitive decline, these results most likely are obtained in mice models that exhibit solely beta-amyloid pathology and may not have the other hallmarks present. With that in mind, we can easily expect the arrest of AD progression and reverse cognitive decline if there are no other components of AD to consider in the progression. My concern is that hallmarks of AD are not subsequent of one another, meaning that just by eliminating beta-amyloid plaques will eliminate inflammation, neurofibrillary tangles, increased microgliosis, etc. For example, in a paper earlier discussed in class, we examined how inflammation could recruit cytokines/chemokines that will initiate signaling cascades that will induce hyper phosphorylation of the tau protein in axons of neurons, which leads to tangles. These tangles lead to the disruption of signals being prorogated down the axon. When neurons are defective in their signaling it can lead to cell death, which means we will still witness the neurodegeneration of an individual without the beta-amyloid factor.

I think in our future we will find that AD will be combated with a combo-therapy treatment. I believe a reduction approach should be taken when discovering therapies and understanding AD. As researchers focus on individual hallmarks, it will allow them to work on individual areas of the puzzle. By success of clinical trials and understanding of the individual hallmarks, will enable researchers the ability to put together the whole puzzle on how to effectively treat AD.

Resources:

http://www.alzforum.org/drg/drc/detail.asp?id=102

http://www.alz.org/

Rojo, et. al Neuroinflammation: Implications for the Pathogenesis and Molecular
Diagnosis of Alzheimer’s Disease. Archives of Medical Research 39 (2008) 1e16