Abstract
BackgroundAging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain’s immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process.MethodsWe have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1+ clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation.ResultsAged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1+ clusters, but not an increase in the number of Iba1+ cells. We have further observed an increase of main inflammatory mediator IL-1β, and an augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch) have been analyzed, showing that there is not a significant increase of CD45+ cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1β) transcription is enhanced in CD45+BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1β expression is further augmented in aged SAMP8 compared to control SAMR1.ConclusionOur data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.
Highlights
Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases
We present the data by using polynomial regression and defining three parameters: critical value of the circle radius; the maximum number of ramification intersections with the circles
We evaluated the expression of Ionized calcium-binding adapter molecule 1 (Iba1) mRNA transcripts in both strains at the different age analyzed and observed that there is a clear decrease in the expression of Aif-1 gene encoding Iba1 in 2 months senescence accelerated mouse prone 8 (SAMP8) animals, in accordance with the results obtained in our immunofluorescence analyses (Fig. 4)
Summary
Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain’s immune response, plays an important role in aged associated degeneration of central nervous system (CNS). Aging is the strongest risk factor for neurodegenerative diseases and while aging in itself is not considered a disease, results in important changes in brain tissue: significant increase in glial activation, complement factors and inflammatory mediators concomitant with brain atrophy [1, 2]. Astrocytes and microglia, undergo cellular hypertrophy with increased expression of cell-surface immune modulatory proteins, including those of the major histocompatibility complex (MHC). These changes are accompanied by increased synthesis and release of pro-inflammatory cytokines and chemokines (reviewed in [11]). Brain myeloid cells (bMyC) mainly comprise microglia cells, and include perivascular, meningeal, and choroid plexus macrophages, peripheryderived monocytes, and brain dendritic cells (bDC), with a role in the establishment of neuroinflammation [12]
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