by Rochelle Fernandes MSc, ND (cand)
The following is a synopsis of Dr. Fernandes’ research. Click here to view the original, full length research paper with references.
Background for Alzheimer’s disease (AD)
Alzheimer’s disease (AD) can stem from a range of physiological, molecular, biochemical, environmental and genetic causes. Physiological causes such as, tumours and cerebrovascular accidents (CVA) can cause vascular and membranous damage that result in a loss of synapses or entire neurons. Chemical causes include hypoxemia and electrolyte imbalances. Environmental causes include drug and metal toxicities, as well as nutritional deficiencies.
There are four major theories that evolved from biochemical, genetic and molecular research:
• The cholinergic hypothesis proposes that decreased activity in cortical, pyramidal neurons affects presynaptic neuron function, and is associated with cognitive decline.
• The genetic hypothesis of Alzheimer’s is associated with autosomal dominant mutations in genes that occur in 0.1% of the population and which contribute to plaque formation.
• The biochemical hypothesis refers to a protein misfolding theory. Amyloid precursor protein (APP) is crucial to neuronal development and repair, however, in Alzheimer’s, abnormal breakdown of APP results in the formation of plaque deposits.
• The last major hypothesis is molecular. Plaques are associated structurally with paired helical filaments (PHF) or straight filaments (SF), of which the main protein present is a crucial microtubule linked protein called tau which mutates and forms neurofibrillary tangles, leading to degradation of neurons.
Diagnosis and symptoms of AD
Symptoms of Alzheimer’s are short term memory loss, inability to concentrate and loss of fine motor control. Progressive symptoms include long term memory loss, difficulties with speech, reading and visual/spatial tasks. Terminal symptoms include delusion, aggression, depression, apathy and incontinence.
Diagnosis of Alzheimer’s is done by a physician through details from the patient and their family members, cognitive/neurological testing (mini mental state exam and electroencephalogram) (MMSE and EEG), brain imaging (PET, SPECT, MRI and CT) and histopathological examination (confirmatory). The National Institute of Neurological and Communicative Disorders and Stroke, the Alzheimer’s Disease and Related Disorders Association and the DSM IV outline how an accurate diagnosis of Alzheimer’s can be made. Memory, attention, perception, language, orientation, problem solving and functional/constructive capabilities are all assessed.
Current therapies in AD
Some valid concerns about the most common therapeutic strategies for neurofibrillary tangles and amyloid plaques are that these are most effective in moderate AD at best, lose effectiveness after six months and have several undesirable side effects. A prophylactic or long lasting therapeutic option is in high demand. Newer candidates for AD treatment include natural agents such as L-carnitine, Gingko biloba, coconut oil, L-phenylalanine; and alternative therapies, such as nucleotide therapies.
Introduction to nucleotide therapy as a novel, future approach to AD
An array of studies in the area of genes and Alzheimer’s disease (AD) have identified several factors that impact the success of treatment. These include age of diagnosis, brain atrophy, cerebrovascular blood flow, rate of cognitive decline, cell death and immune function.
Nucleotide therapy – the use of nucleosides, nucleotides and molecular signalling has been utilized in many diseases, such as arthritis, inflammatory bowel disease and hypercholesterolemia. It is now being incorporated into other more challenging diseases, such as Alzheimer’s that require a more specific, yet, multi-faceted approach to therapy.
Types of nucleotide related approaches in AD
MicroRNA (miRNA), can be used to regulate the expression of genes involved in Alzheimer pathology. Other types of RNA can also be used to modulate genetic expression, such as small interfering RNA (siRNA) and short hairpin RNA (shRNA). P2Y receptor antagonists have been proposed as potential neuroprotective agents in the brain.
In addition to therapeutic nucleotide based approaches, studies have also fostered a role of nucleotide analysis as a preventative tool.
Collectively, it appears that studies have uncovered nucleotides that serve three purposes: a) as identifiers of disease, b) as therapeutic targets, and c) measurement tools of therapeutic response.
Evidence for nucleotide therapy (uncovering mechanisms of action) in AD
Numerous mechanisms of action underlie the use of nucleotides in AD. One approach is the use of nucleotides to alter post transcriptional activity. For instance, impaired miRNA levels are thought to have a role in neurodegenerative disorders. Gene encoding that is thought to be active in inflammation, has also been associated with the pathogenesis of Alzheimer’s. Nucleotides can be used to alter protein expression by creating shRNA plasmids that silence abnormal tau or APP.
One interesting study had some success reducing misfolding in vitro.
Other studies suggested promising therapeutic targets including activation and inhibition of exchange proteins thought to play a major role in Alzheimer’s disease progression.
Applications of nucleotide therapy to other diagnoses
Nucleoside/nucleotide therapy is also successfully used in hepatitis C – a disease that infects almost two hundred million people throughout the world and significantly reduces the quality of life for those who have it. Symptomatic patients display fatigue, jaundice, abdominal pain and arthralgia, however, many HCV patients are non-symptomatic. Therefore, testing is imperative.
HCV is an RNA flavivirus that has six genotypes and more than fifty subtypes. Injection drug use remains the number one method of transmission (parenteral) in Canada. After exposure, there is an incubation period of about six to eight weeks, after which only 15-20% of those with acute infection fully clear the virus, whereas more than 50% go on to develop chronic infection. It is thought that up to 5% can develop liver failure and hepatocellular carcinoma. The mainstay of therapy is Pegylated interferon alpha combined with Ribavirin, however, this only clears the virus anywhere from 40-80%. There is a need for other therapeutic options; perhaps ones that are more affordable, are of shorter duration and have fewer side effects.
Therapeutic efficacy in Hepatitis C is measured by a sustained viral response (SVR). Using a uridine nucleotide analogue inhibitor called Sofosbuvir in combination with the usual therapy achieves an SVR of 90% in patients with genotype 1 and about 100% in patients with genotypes 2 or 3. Duration of therapy is shorter and rates of SVR – at 89 to 90 per cent – are higher.
There is a paradigm shift occurring in that nucleosides/nucleotides are now being considered not only to treat but to determine the success of treatment of Hepatitis C.
Conclusion
Recent research has proposed that nucleotide related therapies can be utilized to: a) identify disease, b) treat, and c) measure therapeutic success. Nucleotide/nucleoside therapy and related molecular approaches have recently been gaining immense success in pathologies, such as Alzheimer’s disease and hepatitis C. The mechanisms of actions and approaches used in applications of nucleotides are very different in these two diagnoses. Nucleoside/nucleotide approaches in AD include using RNA and signalling based mechanisms of action that target post transcriptional regulation and preventing abnormal protein conformations. Approaches in HCV include targeting viral replication, the use of analogues and polymerase inhibition. The use of nucleotide therapy remains fairly novel at this point and further research is needed; more specifically, human trials with greater power. Despite this, nucleotide related therapies have shown immense success in halting disease progression, and could offer great future promise alongside other treatments.
