Amyloid neuropathy, tauopathy, decreased cholinergic and dopaminergic neurons, long-term memory and motor deficits, and sleep disturbance in motopsin deficient mice.

Truncating mutation in motopsin (neurotrypsin/PRSS12) gene causes an autosomal recessive non-syndromic intellectual disability. Since motopsin cleaves agrin, motopsin deficiency causes accumulation of long form agrin. Agrin binds amyloid β (Aβ) and accelerates Aβ fibril formation in Alzheimer's disease (AD). Down's syndrome (DS) exhibits AD-like neuropathological changes. Agrin also contributes to Parkinson's disease (PD). Degeneration of cholinergic neurons is relevant to AD, whereas degeneration of dopaminergic neurons causes PD and PD-associated cognitive impairment and dementia. Although there is a functional relationship between agrin and amyloidosis, it has not been clear whether motopsin deficiency induces amyloid neuropathy or not. Here, motopsin knock-out (KO) mice increased hippocampal amyloid and phosphorylated tau deposits. Agrin and amyloid oligomers were colocalized in the amyloid angiopathy. Motopsin KO mice also exhibited motor deficits. Motopsin KO male mice decreased cholinergic neurons in the vertical limb of the diagonal band of Broca and dopaminergic neurons in the substantia nigra compacta and the ventral tegmental area, and showed long-term memory deficits for object recognition, hypoactivity, and shorter sleeping time. Motopsin KO female mice decreased cholinergic neurons in the medial septum and showed hyperactivity. The results suggest that this intellectual disability is produced by a complex mechanism relating to AD, DS, PD, PD-associated cognitive impairment, and cerebrovascular dementia. The results also suggest that motopsin KO mouse can be a novel animal model for these diseases. Development of therapeutics, that reduce amyloid and phosphorylated tau deposits and protect cholinergic and dopaminergic neurons, will be useful to prevent the progress of this disease.