Cerebellar Molecular and Cellular Characterization in Rat Models of Alzheimer's Disease: Neuroprotective Mechanisms of Garcinia Biflavonoid Complex

Background: Recent evidences suggest that cerebellar degeneration may be associated with the development of Alzheimer's disease (AD). However, previous reports were mainly observational, lacking substantial characterization of cellular and molecular cerebellar features during AD progression. Purpose: This study is aimed at characterizing the cerebellum in rat models of AD and assessing the corresponding neuroprotective mechanisms of Garcinia biflavonoid complex (GBc). Methods: Male Wistar rats were grouped and treated alone or in combination with PBS (ad libitum)/day, corn oil (CO; 2 mL/kgBw/day), GBc (200 mg/kgBw/day), sodium azide (NaN 3 ) (15 mg/kgBw/day) and aluminium chloride (AlCl 3 ) (100 mg/kgBw/day). Groups A and B received PBS and CO, respectively; C received GBc; D received NaN 3 ; E received AlCl 3 ; F received NaN 3 then GBc subsequently; G received AlCl 3 then GBc subsequently; H received NaN 3 and GBc simultaneously while I received AlCl 3 and GBc simultaneously. Following treatments, cerebellar cortices were processed for histology, immunohistochemistry and colorimetric assays. Results: Our data revealed that cryptic granule neurons and pyknotic Purkinje cell bodies (characterized by short dendritic/axonal processes) correspond to indistinctly demarcated cerebellar layers in rats treated with AlCl 3 and NaN 3 . These correlates, with observed hypertrophic astrogliosis, increased the neurofilament deposition, depleted the antioxidant system-shown by expressed superoxide dismutase and glutathione peroxidase, and cerebellar glucose bioenergetics dysfunction-exhibited in assayed lactate dehydrogenase and glucose-6-phosphate dehydrogenase. We further showed that GBc reverses cerebellar degeneration through modulation of neurochemical signaling pathways and stressor molecules that underlie AD pathogenesis. Conclusion: Cellular, molecular and metabolic neurodegeneration within the cerebellum is associated with AlCl 3 and NaN 3 -induced AD while GBc significantly inhibits corresponding neurotoxicity and is more efficacious when pre-administered.