Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology

Abstract

Endosomal-autophagic-lysosomal (EAL) dysfunction is an early and prominent neuropathological feature of Alzheimers’s disease, yet the exact molecular mechanisms contributing to this pathology remain undefined. By combined biochemical, immunohistochemical and ultrastructural approaches, we demonstrate a link between EAL pathology and the intraneuronal accumulation of the β-secretase-derived βAPP fragment (C99) in two in vivo models, 3xTgAD mice and adeno-associated viral-mediated C99-infected mice. We present a pathological loop in which the accumulation of C99 is both the effect and causality of impaired lysosomal-autophagic function. The deleterious effect of C99 was found to be linked to its aggregation within EAL-vesicle membranes leading to disrupted lysosomal proteolysis and autophagic impairment. This effect was Aβ independent and was even exacerbated when γ-secretase was pharmacologically inhibited. No effect was observed in inhibitor-treated wild-type animals suggesting that lysosomal dysfunction was indeed directly linked to C99 accumulation. In some brain areas, strong C99 expression also led to inflammatory responses and synaptic dysfunction. Taken together, this work demonstrates a toxic effect of C99 which could underlie some of the early-stage anatomical hallmarks of Alzheimer’s disease pathology. Our work also proposes molecular mechanisms likely explaining some of the unfavorable side-effects associated with γ-secretase inhibitor-directed therapies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1577-6) contains supplementary material, which is available to authorized users.

Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion

“…It was recently found that βCTF can both be a substrate for autophagic degradation and induce impairment of the autophagic/ lysosomal (29) and endosomal (30) pathways. These results, together with our findings, suggest the presence of a positive feedback mechanism in which a deficit in autophagy leads to increased βCTF levels, which can, in turn, induce further autophagic impairment.…”

Aβ42 oligomers modulate β-secretase through an XBP-1s-dependent pathway involving HRD1

“…This simplistic view of a complex disease has recently drastically evolved. Besides altered ratios in the canonical forms of Aβ40 and Aβ42 that are indeed affected in AD brain39, recent advances on the structural nature (N-terminally truncated and/or C-terminally trimmed4041, biophysical state (monomeric, multimeric, aggregated, fibrillar3442, subcellular localization (intracellular, secreted4344) of Aβ species as well as other βAPP catabolites (C99, AICD511121345, have significantly modified our view of the genuine trigger of the pathology. It arose from these studies that soluble Aβ oligomers (Aβo), appear prior to senile plaques and are now considered to be more toxic than monomeric or fibrillar Aβ.…”

“…BACE1 is considered as a key therapeutic target not only because its inhibition precludes Aβ production but also because BACE-1-mediated βAPP cleavage only, generates C99 that had been shown to trigger cellular perturbations and toxicity even in absence of Aβ in mice models of AD111213. BACE1 is highly expressed in neurons and, unlike is the case for γ-secretase, its expression increases during ageing as well as in the brain of AD patients1415.…”

Alterations in the Balance of Amyloid-β Protein Precursor Species in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

“…Different APP C-terminal antibodies confirmed the 25 kDa CTFη as the predominant band in human CSF. As stated, these APP proteolytic fragments are derived from a constitutive processing step driven by a η-secretase that is partially in dynamic equilibrium with α-and β-secretase-mediated proteolysis (Haass et al, 1992;Willem et al, 2015;Lauritzen et al, 2016). The current canonical views about APPrelated cleavage events are likely a partial understanding of the overall process.…”