Purkinje Neurons: Structural and Functional Changes in Alzheimer's Disease

Objective: This study explored cerebellar involvement in postmortem human and mouse Alzheimer’s disease (AD) brains, as well as cerebellum-essential motor function in transgenic AD mice. Background: There is growing interest in using non-cognitive functional changes as potential predictors of AD. Additionally, increasing evidence suggests the cerebellum may be affected in early stage AD. Loss of cerebellar Purkinje cells has been observed in both familial and sporadic AD. Furthermore, balance and gait impairments are frequent in mild cognitive impairment (MCI) and AD patients. However, research on the functional relevance of the cerebellum in AD remains in its infancy, and the contribution of the cerebellum to AD pathophysiology is unclear. Design/Methods: Human and APPswe/PSEndE9 mouse cerebellar Purkinje neurons were assessed by immunohistochemistry. Locomotor and spatial cognitive functions were evaluated in 4 to 5-month-old APPswe/PSEN1dE9 mice by rotorod, bridge walking, and water maze tests. Aβ plaque and APP processing were determined in APPswe/PSEndE9 mice at different age groups by immunohistochemistry and Western blot. Results: MCI and AD cerebellums exhibited Purkinje neuron loss, as compared with cognitively normal controls. Purkinje neuron loss was found in AD mice as early as 5 months. AD mice demonstrated impairment of balance beam and rotorod performance, but not spatial learning and memory at 4–5 months. Aβ plaque was present in AD mice cerebral cortex at 2 months and significantly increased at 6 and 10 months, while cerebellar plaque was only present at 10 months. Strong intracellular APP staining was observed in AD cerebellum at 2 months. Similar expression of full-length APP and C-terminal fragments was observed in cerebral cortex and cerebellum of AD mice during aging. Conclusions: These results provide neuropathological and functional evidence that cerebellar dysfunction may occur before cognitive impairment in early stages of AD. Furthermore, cerebellar impairment is likely independent of Aβ plaque formation but associated with intracellular APP processing. Disclosure: Mr. Kruse has nothing to disclose. The institution of Kiran Chaudhari has received research support from American Heart Association. Linshu Wang has nothing to disclose. Ali Winters has nothing to disclose. Nathalie Sumien has nothing to disclose. Ritu Shetty has nothing to disclose. Jude Prah has nothing to disclose. Ran Liu has nothing to disclose. Dr. Shi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of Michael Forster has received research support from National Institute on Drug Abuse. Shaohua Yang has nothing to disclose.