Why is the Study of Alzheimer’s Important?
Alzheimer’s disease is important due to its profound impact on individuals and society. It is a progressive neurodegenerative disorder that causes memory loss, impaired thinking, and behavioral changes. With approximately 50 million people affected globally and projections of tripling by 2050, Alzheimer’s poses a growing public health concern.
More than 6 million Americans are living with Alzheimer’s Disease.
1 in 3 seniors dies with Alzheimer’s or another dementia.
It kills more than breast cancer and prostate cancer combined.
In 2023, Alzheimer’s cost the nation $345 billion. By 2050 these costs could rise to $1 trillion.
*Alzheimer’s Association. 2023 Alzheimer’s Disease Facts and Figures.
Our Research and Goals
The broad goal of my lab is to elucidate the pathophysiological mechanisms underlying neurodegenerative disorders such as AD and other dementias by developing and using novel animal models in parallel with studies from affected human subjects.
The LaFerla Lab Four Lines of Research
Amyloid-b(Ab) and tau interaction
All AD cases are marked by the accumulation of two lesions in the brain called plaques and tangles. Plaques consist of a protein called b-amyloid (Ab), whereas tangles consist of a protein called tau that becomes hyperphosphorylated. Understanding the molecular relationship and interaction between Ab and tau and their contribution to cognitive decline remain among the most fundamental and unresolved questions in the AD field. In order to address these important questions, we created the first transgenic mouse model of Alzheimer disease that recapitulates the two major neuropathological lesions, plaques and tangles and referred as the 3xTg-AD mice. Using this innovative animal model, we have made multiple important advances in the AD field to further our understanding of the pathogenic role of Ab and tau and their impact in synaptic and cognitive function. Moreover, it is important to mention that this innovative model has been distributed to researchers throughout the US and the world, producing over 320 publications and providing new insights into the underlying molecular mechanisms driving this insidious disease.
Co-morbities and development of Alzheimer’s disease
My laboratory has a long-standing interest in understanding how co-morbidities influence the onset and progression of Alzheimer’s disease. Sporadic AD patients typically display 2 to 8 different comorbid conditions, and it is possible that these concomitant medical conditions influence the progression of AD. Among the diversity of the different co-morbid conditions, my lab has focused on three: ischemia/stroke, stress and diabetes. Our findings have contributed significantly to understanding how stress and ischemia impact AD pathogenesis. Recently, we discovered that type 1 diabetes requires tau to induced synaptic and cognitive impairments. These observations have led us to investigate if the more common form of diabetes (type 2) also requires tau for the manifestation of the cognitive and synaptic impairments and to further explore the underlying molecular mechanisms by which synaptic integrity is compromised by type 1 and 2 diabetes. These studies have led to a better understanding of the molecular connections by which two highly prevalent human disorders are related, which could facilitate the development of novel interventions for AD patients with diabetes.
Role of inflammation in neurodegenerative disorders
Inflammation is a fundamental protective response, but if it becomes dysregulated, it can be a major co-factor in the pathogenesis of many chronic human diseases, including Alzheimer disease (AD). My laboratory has made important discoveries as to how inflammatory processes trigger AD pathogenesis (including Ab and tau) and impair cognition. Currently, we are investigating the impact of Ab on IL-1b signaling, with an emphasis on the relevance of protein clearance for IL-1b synthesis and protein trafficking for IL-1R1 levels. The translational impact of this work is substantial and significant, as these studies have uncovered new therapeutic targets for the treatment of AD.
Development of novel therapeutic approaches for Alzheimer’s disease
My laboratory has a long track record investigating novel approaches to preventing and treating AD. These include the muscarinic receptor agonist (AF267B), which progressed into human clinical trials due to our work. We have also explored novel small molecules, such as ST101, through which I uncovered an entirely new APP processing pathway that bypasses both a- and b-secretase cleavage of APP, thus precluding Ab production, resulting in a patent. ST101 went on to prevent decline in Phase II clinical trials for AD. Most importantly, my lab has pioneered the use of neural stem cells (NSCs) as a promising therapeutic approach with tremendous potential for AD. Right now, we are investigating the pre-clinical implications of using human neuronal stem cell transplantation in multiple models of neurodegeneration.