A C. elegans model of familial Alzheimer’s disease shows age-dependent synaptic degeneration independent of amyloid β-peptide
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The membrane-embedded γ-secretase complex is involved in the intramembrane cleavage of ∼ 150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38-43-residue secreted amyloid β-peptides (Aβ), with the aggregation-prone 42-residue form (Aβ42) particularly implicated in the pathogenesis of Alzheimer’s Disease (AD). However, whether Aβ42 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin—the catalytic component of γ-secretase—cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to Aβ peptides, apparently through stabilization of γ-secretase enzyme-substrate (E-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new C. elegans models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to Aβ in vivo. We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable E-S complex formation without Aβ42 or Aβ production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another γ-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled γ-secretase E-S complexes in the absence of Aβ production and not by simple loss of proteolytic function. This new C. elegans system provides a powerful platform to study the role of dysfunctional γ-secretase substrate processing in FAD pathogenesis.
SIGNIFICANCE
Dominantly inherited familial Alzheimer’s disease (FAD) is caused by mutations in the enzyme or substrate that produces amyloid β-peptides (Aβ). These mutations alter enzyme processing of substrate to Aβ and can skew production of Aβ to aggregation-prone forms that deposit as pathological plaques. Nevertheless, whether Aβ is the primary driver of AD remains unresolved. Recent evidence supports a model in which loss of neuronal connections in FAD is due to the stalled enzymatic process of Aβ production, rather than the Aβ products. Using the roundworm C. elegans as a genetic model system, we show here that the stalled process itself, rather than Aβ or reduced enzyme activity, can trigger loss of neuronal connections with age in this simple model animal.
