Abstract
The progression of neurodegenerative diseases is reciprocally associated with impairments in peripheral immune responses. We investigated different contexts of selective neurodegeneration to identify specific alterations of peripheral immune cells and, at the same time, discover potential biomarkers associated to this pathological condition. Consequently, a model of human cerebellar degeneration and ataxia -the Purkinje Cell Degeneration (PCD) mouse- has been employed, as it allows the study of different processes of selective neuronal death in the same animal, i.e., Purkinje cells in the cerebellum and mitral cells in the olfactory bulb. Infiltrated leukocytes were studied in both brain areas and compared with those from other standardized neuroinflammatory models obtained by administering either gamma radiation or lipopolysaccharide. Moreover, both myeloid and lymphoid splenic populations were analyzed by flow cytometry, focusing on markers of functional maturity and antigen presentation. The severity and type of neural damage and inflammation affected immune cell infiltration. Leukocytes were more numerous in the cerebellum of PCD mice, being located predominantly within those cerebellar layers mostly affected by neurodegeneration, in a completely different manner than the typical models of induced neuroinflammation. Furthermore, the milder degeneration of the olfactory bulb did not foster leukocyte attraction. Concerning the splenic analysis, in PCD mice we found: (1) a decreased percentage of several myeloid cell subsets, and (2) a reduced mean fluorescence intensity in those myeloid markers related to both antigen presentation and functional maturity. In conclusion, the selective degeneration of Purkinje cells triggers a specific effect on peripheral immune cells, fostering both attraction and functional changes. This fact endorses the employment of peripheral immune cell populations as concrete biomarkers for monitoring different neuronal death processes.
Highlights
Neurodegenerative diseases are generally accompanied by local inflammatory reactions that have been associated with an altered immune cell infiltration into the damaged nervous system (Zlokovic, 2011; Ransohoff and Brown, 2012)
We analyzed the number of leukocytes in olfactory bulb (OB) sections from WT and Purkinje Cell Degeneration (PCD) mice at P25, when the degeneration of mitral cells has not started, and P70, when the death of these cells is in progress (Valero et al, 2006)
The peripheral nature of the leukocytes counted was verified by ascertaining that they were negatively immunostained for TMEM119, which was only expressed by microglial cells (Supplementary Figure 1)
Summary
Neurodegenerative diseases are generally accompanied by local inflammatory reactions that have been associated with an altered immune cell infiltration into the damaged nervous system (Zlokovic, 2011; Ransohoff and Brown, 2012). Changes in the peripheral immune system have been described in Alzheimer’s disease (AD; Ciaramella et al, 2016; Gupta et al, 2018; Le Page et al, 2018), Huntington’s disease (Björkqvist et al, 2008), Parkinson’s disease (PD; Scherzer et al, 2007; Fuzzati-Armentero et al, 2019) and amyotrophic lateral sclerosis (ALS; Liu and Wang, 2017; Zhao et al, 2017) These alterations include changes in the distribution and activation of lymphocytes and macrophages (Lucin and Wyss-Coray, 2009), the latter usually presenting a pro-inflammatory phenotype in humans suffering from neurodegenerative disorders (González and Pacheco, 2014). A better comprehension of peripheral immune responses is becoming essential to understand neurodegenerative diseases to predict, halt or delay their progression
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