Today, dementia such as, Alzheimer’s disease (AD), vascular diseases and motor neurodegenerative diseases, such as Parkinson’s disease (PD), represent a major public health problem. For instance, PD affect to more than 10 million people worldwide and almost 50 million people are affected by dementia. In fact, every year 9,9 millions new patients are diagnosed. Dementia is one of the major causes of disability among elderly people. The mechanisms affecting the disease progression for PD and AD share some common mechanism, such as the immune responses in the neural tissue. The immune system plays a major role in restoring the balance in our organism after injury and is divided in innate and adaptive immunity. The innate immune response is considered the first mechanism responding to the disease stimulus. The activation of the innate immune response can be triggered by different factors and elicit the activation of several cell types. Among the main cell types involved in the innate immune response, we find: microglial cells, astrocytes and oligodendrocytes. Following the innate immune action, the adaptive immune system is activated and B and T cells are recruited by antigen presenting cells to act on the response. The main task of the inflammatory response is to restore the tissue homeostasis after insult. The nature of the insult can vary, going from pathogens to tissue damage. To resolve the injury and restore the balance in the organism, these cells types can secrete a wide array of molecules, such as pro and anti-inflammatory molecules, growth factors and chemokines, all of them involved in the regulation of the innate immune response. The main cell type involved in the inflammatory response in the brain are microglial cells. They are considered the ”macrophages of the brain”. Microglial cells can develop different functions such as: phagocytosis, synaptic remodeling or opsonization. Hence, microglial cell activation is essential for the well function of the brain in disease and healthy brain. One of the main receptors involved in microglial activation are the Toll like receptors (TLR’s). These receptors can recognize, and be activated, by different molecules derived from injured/damages tissue or pathogen derived molecules. Between the different TLR’s, TLR4 is one of the most important due to its capacity to sense bacteria-derived molecules triggering the immune response. Our working hypothesis is focused on the role of the inflammatory response in neurodegenerative diseases with special attention on galectin-3 in the neurodegenerative diseases such as AD and PD. Galectin-3 is a molecule mainly released by microglial cells and involved in different functions including: phagocytosis, microglial activation and cell proliferation.
In the present work, we describe for the first time galectin-3 acting as an endogenous ligand for TLR4 driving the microglial activation towards to a proinflammatory profile. Moreover, the lack of galectin-3 profoundly reduces the microglial activation that might affects to the progression of PD and AD. Furthermore, in our work we found galectin-3 acting as a Triggering Receptor in Myeloid Cells 2 (TREM2) ligand. TREM2 is the main innate immune-related risk factor in Alzheimer’s disease and it is involved in microglial activation, phagocytosis and plaque deposition in Alzheimer disease. Moreover, human TREM2 mutations, such as R47H, are related to a higher susceptibility to developed AD. Despite our efforts, further experiments will be necessary to fully elucidate the role of galectin-3 and its interaction with TREM2 in AD.
Despite the before mentioned, when the inflammatory response start is not well known. In our research line, we aimed to study if the inflammatory response is already present before the typical signs of Alzheimer disease pathology appears. To that aim, we studied the microglial proteomic profile in microglial cells before and after the plaque deposits. We used a specific AD mouse model and we discovered an altered innate immune response already present before the plaque deposition.
In summary, during my work, we have been able to identify an inflammatory role of galectin-3 in PD and AD, with special attention on the role of galectin-3 in the inflammatory response in relation with TLR4 and TREM2 signaling. Furthermore, we evaluated the proteomic profile of microglial cells isolated from AD mouse model before and after the amyloid beta plaque deposits and we found important inflammatory pathways and innate immune proteins altered even before the deposition of the first plaques.
We hope our findings will be further investigated and hopefully be useful to find new potential therapeutic targets and elucidate inflammatory-related mechanisms in neurodegenerative diseases.
- Department of Experimental Medical Science
- Deierborg, Tomas, Supervisor
- Burguillos Garcia, Miguel, Supervisor
- Jakobsson, Johan, Supervisor
|Award date||2017 Dec 14|
|Place of Publication||Lund|
|Publication status||Published - 2017|
Name: Heneka, Michael
Title: MD, PhD
Affiliation: University Hospital of Boon
Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:186
- Alzheimer disease
- Parkinson disease
- innate immune system