Endogenous Aβ causes cell death via early tau hyperphosphorylation

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

“…In addition, calpain-I and caspase 3 protease(s) were only late upregulated and pharmacological inhibition of such apoptotic proteases not only partially protected hippocampal neurons from death after the NGF removal, but also did not significantly interfere with GSK3b-mediated site-specific tau hyperphosphorylation. This suggests that the delayed caspase 3/calpain-I pathway does not regulate GSK3b-dependent changes of tau phosphorylation state, 54 in agreement with previous studies reporting that, in differentiated PC12 induced to cell death by NGF deprivation, the GSK3b kinase inhibition only exerted a small effect on the caspase(s) pathway. 55 An early tau hyperphosphorylation, with a reduction of its microtubule binding affinity has been found in NGF-deprived differentiated PC12 cells.…”

“…Contextually, a progressive disassembly of the cytoskeleton network occurred and the microtubule tracks-based axonal transport was acutely impaired, as shown from observing that mitochondria accumulated in the perykaryon and were no longer transported along axonal processes. 54 The tau-dependent loss of microtubule integrity and axonal neuritic beading associated with jamming of mitochondria were also partially rescued by the treatment with Ab-antibody and GSK3b inhibitors. In addition, calpain-I and caspase 3 protease(s) were only late upregulated and pharmacological inhibition of such apoptotic proteases not only partially protected hippocampal neurons from death after the NGF removal, but also did not significantly interfere with GSK3b-mediated site-specific tau hyperphosphorylation.…”

“…The early, specific and temporally restricted phosphorylation state changes of tau were (1) temporally related to a decrease of the ratio of secreted aAPPs/bAPPs; (2) caused by a deregulation of Akt-GSK3b signaling, known to be in vivo correlated with the onset of AD pathology; (3) mimicked by externally added synthetic Ab1-42 peptide, but not by reversesequence peptide Ab 42-1; (4) sensitive to LiCl treatment and, more importantly, (5) significantly reduced on treatment with Ab antibodies or with b-and g-secretase(s) inhibitors. 54 The increased pool of hyperphosphorylated tau, which is unable to bind microtubules, subsequently detached from them, as shown by the reduction in the intracellular level of acetyl (stable)-tubulin and by a concomitant increase of its a-tyrosinylated (instable) form. Contextually, a progressive disassembly of the cytoskeleton network occurred and the microtubule tracks-based axonal transport was acutely impaired, as shown from observing that mitochondria accumulated in the perykaryon and were no longer transported along axonal processes.…”

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

“…Additional support for a crucial role of tau modifications in NGF-dependent neuronal survival comes from our recent studies (Amadoro et al, 2009). We observe that an early, transient and site-specific GSK-3b-mediated tau hyperphosphorylation (3-6 h after NGF withdrawal)-at two AD-relevant pathological epitopes (Ser262 and Thr231)-is temporally and causally related with an activation of the endogenous amyloidogenic pathway in NGF-deprived hippocampal primary neurons (Matrone et al, 2008b).…”

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

“…Because of these differences, it is argued that human Tau, but not murine Tau, can exert neurotoxic effects. However, this hypothesis is contrasted by data showing that endogenous mouse Tau is required for Aβ-induced postsynaptic dysfunction and behavioral defects, [17][18][19][20][21][22][23][24] which suggest that murine Tau can carry out pathogenic functions that resemble that of human Tau AD.…”