Involvement of saturated fatty acids in the pathogenesis of Alzheimer's disease

Objective of the study The aim of the present study was to establish basic mechanism behind the causal role of fatty acids in the hyperphosphorylation of tau and amyloid beta (A() production, the two main characteristic signatures of Alzheimer's disease (AD) pathology. Results and discussion We found that saturated free fatty acids (FFAs) have no direct effect on the primary rat cortical neurons, in terms of levels of phosphorylated tau and BACE1 protein. This may be attributed to the low capacity of primary neurons to take up and metabolize fatty acids. The primary astrocytes, in contrast, possess a relatively higher capacity to utilize fatty acids. Therefore, we treated rat cortical astrocytes first with FFAs and transferred the conditioned media to treat the cortical neurons. The conditioned media from FFA‐treated astrocytes caused significant increase in the phosphorylation of tau in the cortical neurons. Oxidative stress was found to be involved in the observed FFA‐astrocyte‐induced hyperphosphorylation of tau in neurons. We also found upregulation in BACE1 protein level in cortical neurons. BACE1 cleaves amyloid precursor protein (APP) to form c‐terminal fragment of APP (CTF(), which is neurotoxic. In this context, we found elevated CTF(level in neurons treated with astrocyte‐conditioned medium. CTF(can be further cleaved by (−secretase to produce A(. Conclusion The present study illustrates that elevated levels of saturated FFAs play a central role in the pathological hyperphosphorylation of tau and A(production in AD. Furthermore, our data suggests a critical involvement of astrocytes in mediating the FFA‐induced, AD‐specific effects observed in the neurons.