Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:[53]

β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
γ-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
Selective Aβ42 lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ42 production in favor of other (shorter) Aβ versions.

β- and y-secretase are responsible for the generation of Aβ from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either β- and y-secretase are highly sought after. In order to initiate partial inhibition of β- and y-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.

Immunotherapy. This stimulates the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. One such beta-amyloid vaccine that is currently in clinical trials is CAD106.[54] Immunization with synthetic Aβ1-42 has been shown to be beneficial in mice and displays low toxicity; however human trials have shown no significant differences. Thus, it is not yet effective in humans and requires further research. Specific findings show that the 20 amino acid SDPM1 protein binds tetramer forms of Aβ(1-40)- and Aβ(1-42)-amyloids and blocks subsequent Aβ amyloid aggregation. It is important to note that this study was done in mice and that while it prevents further development of neuropathology it did not result in an improvement in cognitive performance. Lastly, Aβ42 immunization resulted in the clearance of amyloid plaques in patients with Alzheimer's disease but did not prevent progressive neurodegeneration.[55]

Anti-aggregation agents[56] such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.[57] Studies comparing synthetic to recombinant Aβ42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Aβ42 had a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide.[58] This observation combined with the irreproducibility of certain Aβ42 experimental studies has been suggested to be responsible for the lack of progress in Alzheimer’s research.[59] Consequently, there has been renewed efforts to manufacture Aβ42 and other amyloid peptides at unprecedented (>99%) purity[60]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its aggregation[61][62][63] This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.

This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below).[64] Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation.[65] The endocannabinoids anandamide and noladin ether have also been shown to be neuroprotective against amyloid beta in vitro.[66]

It has been shown that high-cholesterol diets tend to increase Aβ pathology in animals. Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.[67]

Chelation therapy, which involves the removal of heavy metals from the body, has also been shown to be beneficial in lowering amyloid plaque levels. This is because Aβ aggregation is somewhat dependent on the metal ions copper and zinc. Zinc in synaptic vesicles, which is under the control of the zinc transporter ZnT3, plays a major role in Aβ formation. The expression of the ZnT3 is significantly lower in Alzheimer’s patients compared to healthy patients. Mice without ZnT3 were found to have much lower plaque formation. Further promoting this concept, Aβ deposition was impeded in APP transgenic mice treated with the antibiotic clioquinol, a known copper/zinc chelator.[67]

Drug therapy has been another approach to treatment. Memantine is an Alzheimer’s drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (NMDA) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of patients with moderate to severe Alzheimer's Disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms in patient population.[68]

Another drug that is currently under research is victoza, which is typically used as a diabetes drug. Treatment with victoza yielded cognitive benefits that included improved object and spatial recognition. Additionally victoza enhances induction and maintenance of long term potentiation (LTP) and paired-pulse facilitation (PPF) in both APP/PS1 and non-genetically altered mice. Other histological benefits include a reduced inflammatory response and an increase in the number of young neurons in the dentate gyrus. The β-amyloid level was also found to be significantly reduced.[69]