Aging, Neurodegenerative Disorders, and Cerebellum

Abstract

An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control. Despite decades of research, the functional contributions of the cerebellum and the underlying molecular mechanisms in aging and neurodegenerative disorders remain largely unknown. Therefore, this review will highlight the molecular and cellular events in the cerebellum that are disrupted during the process of aging and the development of neurodegenerative disorders. We believe that deeper insights into the pathophysiological mechanisms of the cerebellum during aging and the development of neurodegenerative disorders will be essential for the design of new effective strategies for neuroprotection and the alleviation of some neurodegenerative disorders.

Keywords: Alzheimer’s disease; Purkinje cells; aging; brain; cerebellum; dementia; granule cells; inflammation; neurodegeneration; neuron.

Figure 1

Schematic representation of a sagittal section of the cerebellum showing its organization, including cerebellar cells and interconnections between fibers. In the left panel, the fissure is indicated by an arrow, and the folium by a straight bracket. The ML is indicated by the outermost pink band, the PC by the black line, the IGL by the blue band, and the WM by the inner pink layer. In the right panel, a higher magnification of the area boxed in red shows the organization of the layers. Abbreviations used: BS/SC, brainstem/spinal cord; CN, cerebellar nuclei; ML, molecular layer; PC, Purkinje cell layer; IGL, internal granule layer; UBC, unipolar brush cells; WM, white matter.

Figure 2

A timeline of cerebellar development and diseases related to brain development across the human lifespan. Shown are the events of cerebellar development and examples of the related diseases that occur at different perinatal and postnatal stages of human development. Abbreviations used: Cb, cerebellum; GC, granule cells; GCP, granule cell progenitors; PC, Purkinje cells; PCW, post-conception weeks; RL, rhombic lip; VZ, ventricular zone.