Alzheimer’s Disease: Current therapies and future directions
Alzheimer’s disease is a devastating neurodegenerative disorder, which currently affects more than 35 million people worldwide. It is estimated that by 2050 this figure will increase by 204% to a total of 106 million people affected by the disease. (Prince, 2015) Additionally, there is a significant economic and psychological cost associated with the disease that includes the people suffering from it but also carers and family members. Furthermore, the cost for dementia, including direct medical costs and social and informal care, will reach 2 trillion US dollars by 2030 (Prince, 2015).
Clinically, the disease is characterized by memory loss, cognitive impairment, and difficulties in performing simple everyday tasks. In the later stages, depression and aggressive behaviour are also common symptoms. The pathological features of the disease are attributed to the malformation of two proteins that form aggregates inside and outside cells. The former are caused by a hyperphosphorylated form of the protein Tau, while the latter occur after misprocessing of the amyloid precursor protein (APP), producing toxic Aβ oligomers. These aggregates then cause neuronal cells to malfunction or even die, while inhibiting the ability of the brain to produce new neurons (Long and Holtzman, 2019).
Currently, there are no drugs or predictive prognostic markers available that can alter or detect the onset or the course of the disease, and the approved therapies can only alleviate some of the pathological symptoms of the disease. At present, there are four drugs that are used for people suffering from Alzheimer’s disease. Three of these (donepezil, galantamine and rivastigmine) act as acetylcholinesterase inhibitors and the other one (memantine) as an N-methyl-D-aspartate receptor (NMDA) antagonist. The inhibitors of the enzyme acetylcholinesterase help increase the availability of acetylcholine, an important neurotransmitter, at the synapse, whereas the drug that blocks the NMDA receptor reduces the excitotoxicity effects of L-glutamate (Lane, Hardy and Schott, 2018). Even though these drugs can alleviate some of the symptoms of the disease, it is important for future efforts to be directed to discovering novel disease-modifying drugs or therapies, which reverse or fully block the progress of the disease. It is estimated, for example, that if a drug can slow the onset of the disease by 5 years, this would translate into 469,000 fewer people living with dementia by 2030 and £21.2bn/year less money spent by 2050 in the UK (Lewis et al., 2014).
In the EuroNeurotrophin Consortium, we have focused our research on developing and testing novel small molecules, mimetics of endogenous neurotrophins, as well as isolated natural products from marine bacteria and/or fungi from the East Mediterranean basin that act as mimetics of neurotrophins, that can be used as drugs against Alzheimer’s disease. Furthermore, evidence clearly shows that neurotrophin processing and expression levels are deregulated in Alzheimer’s Disease (AD), and this has been postulated to contribute to the disease pathology (J. Allen, J. Watson and Dawbarn, 2011). To this end, we use a variety of Alzheimer’s disease models (in vitro and in vivo), as well as novel techniques and interdisciplinary approaches, in order to design and biologically identify a lead drug that will hinder disease progression.
About the Author
ESR11: Thanasis Rogdakis
Thanasis’s research focuses on novel synthetic or naturally derived microneurotrophins that he is testing for their ability to activate neurotrophin receptors. Compounds that present favourable pharmacokinetic profiles will be further studied in Alzheimer’s Disease models in vitro and in vivo.