Morphological impairments in microglia precede age-related neuronal degeneration in senescence-accelerated mice

Abstract

The ageing brain is characterized by degenerative changes in both neurons and glia. Although neurons are known to lose dendritic complexity with ageing, age-related changes in the morphology of microglia have not been well documented. We investigated potential age-related changes in microglial morphology using mouse models. Senescence-accelerated mouse prone 10 (SAMP10) in which neuronal degeneration begins to appear around 8 months of age and becomes progressively remarkable with advancing age was used as a model of brain ageing. Senescence-accelerated mouse resistant 1 (SAMR1) in which age-related neuronal changes are inconspicuous was used as usual-ageing controls. Hippocampal sections prepared from 3-, 8- and 14-month-old SAMP10 and 3-, 8-, 14- and 24-month-old SAMR1 mice were stained immunohistochemically with anti-Iba-1 antibody to highlight microglia. Stick figures of individual microglia reflecting the length and complexity of cytoplasmic processes were made by camera lucida drawing. Parameters representing morphological features of microglia were quantified using an image analyzer: area of convex closure, cell body area, number of primary processes, maximal branch order, combined projection length, number of segments and number of tips. Pathological changes of processes such as beading and clusters of fragmented twigs were counted. In microglia of 3- and 8-month-old SAMP10 mice, combined projection length was shorter and numbers of segments and tips were smaller than those in age-matched SAMR1 mice. Similar changes were detected in SAMR1 mice at age 14 months and older. Microglia of SAMP10 mice at all ages were characterized by having frequent pathological changes in processes, which were not remarkable in SAMR1 mice at any age. These morphological abnormalities in microglia of SAMP10 mice preceded the onset of neuronal degeneration and may lead to making brain tissue less protective to neurons. We propose that preceding abnormalities in microglia may contribute to the vulnerability to age-related neuronal degeneration in SAMP10 mice.

Histological Architecture Underlying Brain–Immune Cell–Cell Interactions and the Cerebral Response to Systemic Inflammation

“…Given that microglia are neuroprotective, it is reasonable to consider that aging-related, progressive microglial degeneration, and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic AD (86). This idea is also supported by our own findings on microglial aging in SAMP10 mice (87). …”

Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model

“…As such microglia priming is considered an important confounding factor in age-associated neurodegenerative diseases [79, 80]. On the other hand, dystrophic microglia, characterized by loss of structural integrity, presence of spheroid inclusions and fragmented cellular processes have been reported in the aged human brain [81] or in rodent mouse models of accelerated aging and neurodegeneration [82, 83]. Since dystrophy in microglia is restricted to aged and neurodegenerative brain tissues, it has been proposed to be the consequence of age-associated telomere shortening and replicative senescence in microglia [36].…”

The Anti-brain Ageing Effects of Krill Phosphatidylserine in SAMP10 Mice

“…According to the former studies about microglial cells morphology in age-related disease, researchers have observed that microglia become activated in aged rats (Ogura et al, 1994;Kawamata et al, 1998). Quantitative analysis has shown that abnormalities of microglia in the early stage may cause the SAMP10 mice vulnerable to age-related neuronal degeneration (Hasegawa-Ishii et al, 2011). Iba-1, a marker of microglial activation (Ahmed et al, 2007), was evaluated in this paper; the results showed that K-PS low significantly downregulated the expression of Iba-1 which indicated that activated microglial cells were inhibited to a certain extent.…”