The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration

Abstract

Recently, we have shown that the microtubule-associated protein tau is essential for ␤-amyloid (A␤)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates A␤-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated A␤ induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced A␤-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that A␤-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate A␤-induced neurotoxicity.

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…Both tau fragmentation and neurotoxic effects of A␤ could be diminished by calpain-1 inhibition. 186 To date, however, no direct proof for the suggested neurotoxicity of the 17-kD tau fragment has been provided.…”

“…Interest in tau is growing, especially after discovery of several tau mutations in FTDP-17 and in light of recent reports that suggested tau as a downstream mediator of a␤-conferred toxicity. 186,226 Counteracting tau neurotoxicity will therefore be a promising strategy, and even more so when combined with anti-A␤ directed approaches.…”

Formaldehyde increases intracellular calcium concentration in primary cultured hippocampal neurons partly through NMDA receptors and T-type calcium channels

“…Tissue-derived endogenous formaldehyde even at such a low concentration can induce pain behavior [7,22] . Previous studies have demonstrated that formaldehyde exposure at 0.01-0.1% (~3.3 to ~33 mmol/L) induces mis-folding and aggregation of tau protein in hippocampal neurons [9] , which is essential to beta-amyloidinduced neurodegeneration [23] . Cognitive impairments in senile dementia have also been associated with elevated endogenous formaldehyde concentration [10] .…”

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

“…AβOs, which are increasingly considered to act as proximal neurotoxins in AD, interact with glutamate receptors at the dendritic membrane, induce abnormal calcium influx and oxidative stress, block long-term potentiation (LTP), and facilitate long-term depression, ultimately leading to synapse failure [3,4] . It has recently been suggested that the deposition of Aβ might trigger a series of cellular events that lead to posttranslational changes in Tau followed by neurite degeneration [2,5] . Furthermore, experiments in both cultured rodent hippocampal neurons and transgenic mice demonstrate that Tau is intrinsically involved in Aβ-mediated neuronal dysfunction and cell death [6,7] .…”

“…Taken together, the data suggest that there is an intrinsic relationship between Aβ and Tau dysfunction. It has been shown that the deposition of Aβ induced the activation of calpain-1 and caspase-3 proteases [2,5,8] . These proteases cleave Tau proteins at specific sites, generating toxic Tau fragments or enhancing the aggregation properties of Tau protein [2,5,9] .…”