Summary: As the brain ages, microglia adopt dysfunctional states that increase the risk of developing neurodegenerative diseases such as Alzheimer’s disease.
Scientists from the Trinity Biomedical Sciences Institute (TBSI) have shed new light on aging processes in the brain. By linking the increased presence of specialised immune cells to conditions such as Alzheimer’s disease and traumatic brain injury for the first time, they have unearthed a possible new target for therapies aimed at treating age-related neurological diseases.
The research, which benefited from a collaboration with experts at the University of Maryland School of Medicine and focused on microglia in the brain and spinal cord, is published today in the leading international journal, Science Advances.
Microglia are a unique type of immune cell whose job it is to support nerve cells, defend against invading microbes, clear debris and remove dying nerve cells by engulfing and eating them. Emerging research indicates that microglia can have different functional responses depending on molecular and biochemical changes occurring within these specialized cells.
In fact, various subtypes of microglia can be distinguished based on a property called autofluorescence. This is the tendency of cells to emit light of one color after they have absorbed light of another, and it occurs because specific substances inside the cells absorb light. The substances stored in specialized cellular compartments include fat molecules, cholesterol crystals, metals and other misfolded proteins.
David Loane, Assistant Professor of Neuroscience in Trinity’s School of Biochemistry and Immunology in TBSI is the lead author of the research. He said:
“As the brain ages, these materials build up inside autofluorescent microglia, which increase their autofluorescence as a result. Unfortunately, this accumulation of cellular debris also makes it harder for the microglia to perform their essential garbage collection tasks in the brain and to prevent neurological injury and neurodegenerative disease.
“In this study we found – in aged animals – that these microglia adopt a unique, dysfunctional state, which has a number of problematic impacts. For example, there is an increase in cellular stress and damage, an accumulation of fats and iron, alterations to metabolic processes and an increase in production of molecules that over-egg the immune response.”
In addition, the scientists demonstrated that autofluorescent microglia and associated inflammation were more pronounced under pathological conditions, such as in genetic risk factor models of Alzheimer’s disease, and – promisingly – were reversed by drug-assisted microglial replacement in aged animals.
Prof Loane added:
“Furthermore, environmental exposure to acute traumatic brain injury in animals accelerated the age of onset and tissue-wide distribution autofluorescent microglia by increasing oxidative stress damage in the brain of injured animals.
“As a result, increasing evidence now suggests that the accumulation of autofluorescent microglia contributes to diseases of aging and neurodegeneration. If these sub-populations of microglia are highly inflammatory and damaging to the brain, then targeting them could be a new strategy for treating aging-related diseases.”
About this aging and neuroscience research news
Author: Thomas Deane Source: TCD Contact: Thomas Deane – TCD Image: The image is in the public domain
Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration
Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age.
Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months old) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress.
Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction.
Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia.
Furthermore, increased phagocytic activity, lysosomal burden, and lipid accumulation in microglia persisted for up to 1 year after TBI, were modified by APOE4 genotype, and chronically driven by phagocyte-mediated oxidative stress.
Thus, AF may reflect a pathological state in aging microglia associated with increased phagocytosis of neurons and myelin and inflammatory neurodegeneration that can be further accelerated by TBI.