A γ-adducin cleavage fragment induces neurite deficits and synaptic dysfunction in Alzheimer’s disease

•AEP age-dependently cleaves γ-adducin at N357 in AD.•The AEP-generated γ-adducin (1-357) fragment translocates into nucleus and inhibits neurites growth.•γ-adducin (1-357) fragment induces neurites deficits and synaptic dysfunction by downregulating Rac2.•γ-adducin (1-357) fragment promotes AD-like pathology and cognitive impairments in vivo. Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer’s disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD.