A New Hope for Neurodegeneration

Author: Devon Sheppard Edited by: Inês Barreiros

Today we enjoy a greater global life expectancy than ever before. The United Nations estimates that the global population of those over 60 years of age is estimated to increase by over 50%, from the current ~ 900 million to 1.4 billion by 2030, with the over 80 population being the largest segment of that growth (1).  With this life span increase and an ageing population, the quality of health in the later years of life has become a developing concern. 

One of the most costly and problematic diseases impacting this growing elderly population is dementia. According to Alzheimer’s Disease International, the number of sufferers from dementia is projected to double by 2030 to 74.7 million, the majority of which are classified as Alzheimer’s Dementia (AD) . Alzheimer’s Disease is particularly costly in terms of the extensive social care required for people with dementia, as well as the personal cost for those afflicted and their loved ones. Despite the fact it was discovered over a century ago by Dr. Alois Alzheimer, we are yet to see the development of a pharmaceutical approach to successfully treat this debilitating disease. Our understanding of the progression and pathology of AD has become clearer with research but this has not been reflected in an accompanying traction with therapeutics.


Our current understanding of the disease places the amyloid-beta protein at the heart of cognitive decline. It was during the 1980s that both amyloid-beta and tau proteins were identified for their role in the gross morphological changes that occur within the brain during the progression of AD. These changes, now considered a hallmark of the disease, are the formation of plaques and neurofibrillary tangles in the brain. However, even as early as 2002, there was evidence of synaptic and cognitive changes occurring prior to the formation of plaques, due to the presence of toxic, soluble oligomers of the amyloid-beta proteins (2).  It is thought that the plaques and tangles act as reservoirs for the toxic components of amyloid-beta. While many therapeutic approaches have been hypothesised in relation to processing and accumulation of beta-amyloid, none has so far developed into clinical therapies.


Shortly after the discovery of amyloid-beta and tau in AD, a drug called tacrine was developed for AD and it was the first one to be approved for use in the treatment of Alzheimer’s. Memantine, which works on the neurons in a different way than tacrine, was the next drug to be approved for treatment.  Both of these drugs, and the repertoire of pharmacological targets for treatment that followed after, remain focused on neurotransmitters. While the impact of the existing treatments vary among sufferers, they share a method of compensating for loss of connectivity and death of neurons that continues to progress in AD but do not address the underlying destruction of tissue. While the relief of symptoms, however temporary, may be of great comfort to patients, the disease continues to destroy neural tissue towards a fatal end. Therefore, there is an imperative need for effective therapies which will reduce the progression of AD and slow or halt the destruction of neurons that result in cognitive decline.


One of the more unique avenues into novel therapeutics recently came out of Massachusetts Institute of Technology (MIT). Using an AD mouse model, researchers were able to induce gamma waves in the brains of mice that were susceptible to develop Alzheimer’s (3). Neural gamma waves are thought to help us perceive and understand our environment and it has been known for some time that they are disrupted in AD. This may be in part due to disruption in the cellular network from the widespread synaptic loss and neuron connectivity that occurs in early stages of the disease and correlates with cognitive disruption (4).  The MIT researchers used optogenetics to produce the gamma waves. This means they introduced a light responsive protein to the brain and sent pulses of light to this protein through an optical fiber they had implanted beforehand. This process created a specific light response in selected regions of the brain.  

The induced gamma waves-based treatment applied in the AD mouse model significantly reduced plaque and total amyloid-beta concentration. This was accompanied by reduction in the production of amyloid-beta protein and changes in the tau protein that is responsible for keeping the structural frame of the cells intact. A considerable part of this reduction in toxic protein was attributed to the effect this induction had on microglia, the immune cells within the central nervous system. Overall, the microglia were more effective in clearing plaques. The same effects were found to be produced in the visual cortex, suggesting that the method is broadly applicable. The potential for the development of non-invasive therapies from this work opens incredible possibilities for the future of AD treatment and care.

Dr Tsai and Dr Boyden of the MIT study joined other leading scientists in the foundation of the company Cognito Therapeutics; dedicated to the development of therapeutics for neurodegenerative diseases. This includes their recent work with induced gamma waves. There is still considerable research to be done in the process of translating these remarkable results in the mouse model to clinical application in humans. The development of this company by Dr Tsai and Dr Boyden has allowed those involved in the initial discovery to shepherd its progression towards implementation in human health, smoothing the transition from basic research to human health application. Such a novel approach, guided by the initial researchers, truly represents a new hope for the future of Alzheimer's Disease treatment.

 

(1)  United Nations, Department of Economic and Social Affairs, Population Division(2015), World Population Ageing]

(2) Hardy J, et al Science (2002) 297, 353-356 

(3) Iaccarino H, et al, Nature (2016) 540,230-235

(4) Terry R, et al, Annals of Neurology (1991) 30, 572-580