LOSS OF F-ACTIN IN SYNAPTOSOMES CORRELATES WITH COGNITIVE DYSFUNCTION (BRAAK STAGING, B-AMYLOID LOAD AND TANGLE LOAD) IN PATIENTS WITH MCI AND AD

Abstract

Alzheimer's disease (AD) has been described by its biological signatures that mediate synaptic dysfunction and loss of dendritic spines. Neuronal cytoskeletal protein, such as F-actin (filamentous actin) are critical modulator of dendritic spine morphology and also regulates its function. Thus, maintaining the ratio of F-actin and G-actin within the dendritic spines is essential for optimal synaptic function. Our aim was to determine the status of synaptic F-actin levels in postmortem tissue from patients with no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD patients. Autopsy human brain tissues were obtained from Rush Alzheimer's Disease Center, Chicago, IL, USA. Total of 36 brains were examined (12 each of NCI, MCI and AD). Frontal neocortical tissue from each human brain was thawed on ice and used for the preparation of synaptosomes. Further, we used an innovative method to isolate highly enriched F-Actin and G-Actin fractions from synaptosomes. F-actin levels in synaptosomes prepared from NCI, MCI and AD postmortem tissue showed graded decrease were significantly correlated. Furthermore, significant correlation was also seen between the decrease in synaptosomal F-actin and poor performance in several cognitive tests (Global cognitive score, Episodic memory score, Working memory score) as also reflected Braak staging, b-amyloid load and tangle load. Our findings provide evidence that loss of F-actin at the synapse correlates with the histopathological and behavioral dysfunctions seen in patients with mild cognitive impairment (MCI) and AD.