MECHANISMS OF BDNF DOWN-REGULATION BY THE PATHOLOGICAL CORRELATES OF ALZHEIMER’S DISEASE

Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder that is the leading cause of dementia among the elderly. Alzheimer’s disease presents as global cognitive decline with associated memory loss and altered personality. The neuropathological hallmarks of Alzheimer’s disease include extracellular beta-amyloid-containing plaques and intracellular neurofibrillary tangles formed by hyper-phosphorylated tau protein. There is increasing evidence that although the primary insult in Alzheimer’s disease may be over-expression of amyloid-β, it may ultimately lead to cognitive dysfunction and neurodegeneration by inducing alterations in tau. While the precise toxic mechanism of these accumulated proteins is not well understood, our hypothesis is that both amyloid-β and tau exert their neurotoxicity via down-regulation of brain-derived neurotrophic factor (BDNF). BDNF is crucial for synaptic function, neuronal survival and learning and memory and is decreased in Alzheimer’s disease, tauopathies and in several relevant animal and cellular models of Alzheimer’s disease. Using differentiated, human neuroblastoma cells, we found that treatment with oligomeric Aβ down-regulates basal levels of BDNF as a consequence of Aβ-induced CREB transcriptional down-regulation. Similarly, these cells, when made to over-express wild-type tau, also exhibit reduced BDNF expression. They specifically lose the major CREB-regulated BDNF transcript, transcript IV. Using transgenic mice, we showed that neither tau mutations nor neurofibrillary tangles are required for BDNF reduction, but that wild-type tau over-expression is sufficient to down-regulate BDNF. Lastly, we crossed APP23 mice, which over-express Aβ and exhibit reduced BDNF, with Tau knockout (TauKO) mice. BDNF levels were partially rescued in the APP23xTauKO animals, indicating that tau is an intermediate in Aβ-induced BDNF down-regulation. These results demonstrate that both soluble Aβ and tau down-regulate BDNF, which likely contributes to learning and memory deficits. Furthermore, the partial rescue of BDNF levels by tau knockout suggests that tau contributes to Aβ-induced BDNF down-regulation. Thus, loss of BDNF may mediate tau neurotoxicity down-stream of Aβ, which has profound implications for therapeutic intervention in Alzheimer’s disease and tauopathies, suggesting that current treatments used to alleviate AD symptoms by targeting Aβ pathology alone may not be sufficient, and that combined treatments targeting tau may be required.