Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging

Abstract

To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.

Environment matters: microglia function and dysfunction in a changing world

“…This pattern is striking given growing recognition that some neuropsychiatric disorders are linked to an underlying vulnerability, which likely begins perinatally, and a “second hit” that unmasks the full pathology [39]. Microglia are ideal candidates as a mechanism underlying priming, as they are macrophages that shift their function following immune stimulation, potentially permanently, in common with many immune cells; but they are also long-living cells [40,41], in contrast to most innate immune cell populations outside the brain. Notably, infection at a later stage of development, postnatal day (P)30, does not have the same persistent impact, implicating a critical window [42].…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Microglia are long‐lived cells with a relatively low turnover. By genetically labeling microglia in pathogen‐free mice it was recently determined that microglia can survive during the whole lifespan of an animal, and can thus exert crucial long‐lasting influences on neurodegenerative disorders (Fuger et al, ). However, it is well documented that microglia can be self‐regulated without contribution from peripheral myeloid cells and their turnover is tightly controlled by the coupling of apoptosis, with approximately 1% murine microglia dying in 1 day and the whole population of cells renewing several times throughout life (Askew et al, ; Tay et al, ).…”

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

“…In contrast to the lattice-like organization of sparsely (< 0.5%) renewing microglial cells in the adult brain [3, 26, 27, 35, 43], heightened microglial reactivity and microgliosis are hallmarks of all neurodegenerative diseases regardless of severity, as exemplified in local neuronal damage and widespread neurodegeneration [10, 13, 32, 37, 43]. …”