Microscopy image of the cerebellum of a two-year-old (aged) mouse with striped Purkinje cell loss. The cerebellum expresses green fluorescent protein specifically in Purkinje cells. The bright green stripes are composed of surviving Purkinje cells, and the dark stripes indicate degeneration. Image credit: (CC BY-SA 4.0)
Aging involves the gradual loss of brain cells and a decline in physical and cognitive capabilities. One brain region affected by aging is the cerebellum, which is best known for its role in motor coordination.
During healthy aging, the cerebellum is reduced in size, and elderly individuals often face difficulties with balance and motor skills. This shrinkage is partly caused by the loss of neurons, particularly Purkinje cells. A reduction in Purkinje cells and impaired motor function have also been seen in rodents during normal aging.
Furthermore, in many rodent models of disease, not all Purkinje cells are equally likely to die. The surviving cells form specific patterns similar to those seen during cerebellar development. However, it has so far been unclear whether such regional differences in Purkinje cell loss also occur during healthy aging. Addressing this question would shed light on how aging influences cellular susceptibility and resilience in the cerebellum and how these cellular responses affect motor function and age-related cell death.
To find out whether loss of Purkinje cells in aged mice occurs in a similar pattern observed during disease, Donofrio et al. used a combination of genetic, histological, and imaging techniques to visualize Purkinje cells in the cerebellum.
The results revealed that the loss of Purkinje cells in healthy aged mice occurred in a pattern similar to that often observed in models of disease. However, the overall pattern in aged mice was distinct and occurred in a parasagittal, striped pattern – that is, long, narrow, and running front-to-back through the cerebellum. In addition, examining human cerebellum tissue samples collected from individuals without any reported neurological or neuropsychiatric problems confirmed a loss of Purkinje cells that increased with age. However, a specific pattern remains to be confirmed.
Our study reveals a cerebellar framework of vulnerability and resistance to age-related cell death. These findings could enhance healthy brain aging by improving the precision of targeted therapeutics and opening avenues for preventative strategies to reduce or prevent cell loss. The essential step is to fully understand when and how cerebellar neurons degenerate across the human lifespan.
