Abstract
Although familial Alzheimer disease (AD)-associated autosomal dominant mutants have been extensively studied, little is known about the underlying molecular mechanisms of neurodegeneration induced by these mutants in AD. Wild-type, Swedish or London amyloid precursor protein (APP) transfection in primary human neurons induced neuritic beading, in which several co-expressed proteins, such as enhanced green fluorescent protein, red fluorescent protein (RFP)-tau and RFP-ubiquitin, accumulated. APP-induced neuritic beading was dependent on caspase-6 (Casp6), because it was inhibited with 5 μM z-VEID-fmk or with dominant-negative Casp6. Neuritic beading was independent from APP-mediated amyloid β-peptide (Aβ) production, because the APPM596V (APPMV) mutant, which cannot generate Aβ, still induced Casp6-dependent neuritic beading. However, the beaded neurons underwent Casp6- and Aβ-dependent cell death. These results indicate that overexpression of wild-type or mutant APP causes Casp6-dependent but Aβ-independent neuritic degeneration in human neurons. Because Casp6 is activated early in AD and is involved in axonal degeneration, these results suggest that the inhibition of Casp6 may represent an efficient early intervention against familial forms of AD. Furthermore, these results indicate that removing Aβ without inhibiting Casp6 may have little effect in preventing the progressive dementia associated with sporadic or familial AD.
Highlights
The high levels of active Casp[6] in familial Alzheimer disease (AD) brain[1] incite the question of whether familial AD-associated mutant proteins induce Casp[6] activation and if this activation depends on amyloid b-peptide (Ab)
When APPWT, APPSw or APPLo were co-expressed with enhanced green fluorescent protein (EGFP), EGFP was often detected in an enlarged cell soma and appeared as beads-ona-string within the neurites (Figure 1b–d)
Neuritic EGFP-positive beads overlapped with a slight enlargement and darkened area of the neurite resembling varicosities, in the absence of compromised membrane integrity (Figure 1e)
Summary
The high levels of active Casp[6] in familial AD brain[1] incite the question of whether familial AD-associated mutant proteins induce Casp[6] activation and if this activation depends on Ab. Expression of the APP Swedish (Sw) mutation increases the vulnerability of transfected PC12 cells to oxidative stress and the cells undergo Casp3-dependent cell death.[10] Because familial mutants increase amyloid b-peptide (Ab) production, Ab is generally thought to cause AD by synaptic or neuronal toxicity (reviewed in Selkoe and Podlisny[11]). Casp[6] has been recognized as highly important in inducing axonal degeneration, whereas Casp[3] induces cell death in APP-mediated death receptor 6 signaling in trophicfactor-deprived commissural, sensory and motor mouse neurons.[21] active Casp[6] cleaves several neuronal proteins associated with AD, such as APP, tau,[22] and presenilin 1 and 2,23 Casp[6] cleaves crucial cytoskeleton proteins including a-Tub, and a-actin-regulating post-synaptic density proteins, drebrin, spinophillin, a-actinin-1 and -4.4 the activation of Casp[6] may alter the neuronal cytoskeleton and be responsible for the abundant levels of dystrophic neurites present in AD brains
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