P3‐136: Tau cleavage by calpain: The intermediate at Mr 17kD / MW 11kD is metastable but not toxic

Background: Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. These inclusions together with the extracellular Abeta deposits constitute the neuropathological characteristics of Alzheimer’s disease (AD). AMP-activated protein kinase (AMPK) is a metabolic sensor involved in the regulation of intracellular energy metabolism. AMPK is a heterotrimeric Ser/Thr protein kinase activated via Thr-172 phosphorylation of the alpha-subunit. Recently, we found that AMPK activation can lower Abeta accumulation by triggering autophagy. Our results also showed that AMPK can be activated in cell lines and in vivo in mouse brain by resveratrol and more potent analogues to lower Abeta accumulation. AMPK controls neuronal maintenance and is over activated during metabolic stress. Whether AMPK over activation is neuroprotective or neurotoxic is, however, a matter of debate. Here, we asked whether AMPK is deregulated in AD and other tauopathies and whether AMPK can control tau phosphorylation. Methods:Levels of activated AMPKwere assessed in postmortem brain samples in AD and other tauopathies by immunohistochemistry using antibodies specific for phospho-Thr-172 AMPK. In vitro phosphorylation assays were employed to determine whether AMPK can phosphorylate tau. Results: We found that the activated form of AMPK (phosphorylated at Thr-172, p-AMPK) is abnormally accumulated in neurons in 3R+4R and 3R tauopathies, such as AD, Guam Parkinson dementia complex, Pick’s disease, and front temporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. In AD brains, p-AMPK decorated neuropil threads and dystrophic neurites surrounding amyloid plaques. Granular p-AMPK immunoreactivity was also observed in neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. P-AMPK was not found in purified PHFs, indicating that p-AMPK did not co-aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Conclusions: Although it remains to be determined whether AMPK activation is detrimental or neuroprotective in tauopathies, our data suggest that, by controlling tau phosphorylation, AMPK might be critical for the neurodegenerative process of these diseases.