Cerebellar Amyloid-β Plaques: Disturbed Cortical Circuitry in AβPP/PS1 Transgenic Mice as a Model of Familial Alzheimer's Disease

Cerebellar amyloid-beta (A beta) deposition in the form of neuritic plaques and Purkinje cell loss are common in certain pedigrees of familial Alzheimer's disease (FAD) mainly linked to PS1 mutations. A beta PP/PS1 transgenic mice, here used as a model of FAD, show a few A beta plaques in the molecular layer of the cerebellum at 6 months, and which increase in number with age. Motor impairment is apparent in transgenic mice aged 12 months. Combined methods have shown degenerated parallel fibers as the main component of dystrophic neurites of A beta plaques, loss of synaptic contacts between parallel fibers and dendritic spines of Purkinje cells, and degeneration of granule cells starting at 12 months and increasing in mice 18/20 months old. In addition, abnormal mitochondria and focal loss of Purkinje and basket cells, together with occasional axonal torpedoes and increased collaterals of Purkinje cells in mice aged 18/20 months, is suggested to be a concomitant defect presumably related to soluble extracellular or intracellular A beta. These observations demonstrate serious deterioration of the neuronal circuitry in the cerebellum of A beta PP/PS1 transgenic mice, and they provide support for the interpretation of similar alterations occurring in certain pedigrees with FAD.