Early Loss Of Cerebellar Purkinje Cells In Human And A Transgenic Mouse Model Of Alzheimer'S Disease

Background: The cerebellum's involvement in AD has been under-appreciated by historically labeling as a normal control in AD research. Methods: We determined the involvement of the cerebellum in AD progression. Postmortem human and APPswe/PSEN1dE9 mice cerebellums were used to assess the cerebellar Purkinje cells (PC) by immunohistochemistry. The locomotor and spatial cognitive functions were assessed in 4- to 5-month-old APPswe/PSEN1dE9 mice. A beta plaque and APP processing were determined in APPswe/PSEN1dE9 mice at different age groups by immunohistochemistry and Western blot. Results: We observed loss of cerebellar PC in mild cognitive impairment and AD patients compared with cognitively normal controls. A strong trend towards PC loss was found in AD mice as early as 5 months. Impairment of balance beam and rotorod performance, but no spatial learning and memory dysfunction was observed in AD mice at 4-5 months. A beta plaque in the cerebral cortex was evidenced in AD mice at 2 months and dramatically increased at 6 months. Less and smaller A beta plaques were observed in the cerebellum than in the cerebrum of AD mice. Similar intracellular APP staining was observed in the cerebellum and cerebrum of AD mice at 2 to 10 months. Similar expression of full-length APP and C-terminal fragments were indicated in the cerebrum and cerebellum of AD mice during aging. Discussion: Our study in post-mortem human brains and transgenic AD mice provided neuropathological and functional evidence that cerebellar dysfunction may occur at the early stage of AD and likely independent of A beta plaque.