Cuprizone drives divergent neuropathological changes in different mouse models of Alzheimer's disease

Myelin degradation is a normal feature of brain aging that accelerates in Alzheimers disease (AD). To date, however, the underlying biological basis of this correlation remains elusive. The amyloid cascade hypothesis predicts that demyelination is caused by increased levels of the {beta}-amyloid (A{beta}) peptide. Here we report on work supporting the alternative hypothesis that early demyelination is upstream of amyloid. We challenged two different mouse models of AD (R1.40 and APP/PS1) using cuprizone-induced demyelination and tracked the responses with both neuroimaging and neuropathology. In oppose to amyloid cascade hypothesis, R1.40 mice, carrying only a single human mutant APP (Swedish; APPSWE) transgene, showed a more abnormal changes of magnetization transfer ratio and diffusivity than in APP/PS1 mice, which carry both APPSWE and a second PSEN1 transgene (delta exon 9; PSEN1dE9). Although cuprizone targets oligodendrocytes (OL), magnetic resonance spectroscopy and targeted RNA-seq data in R1.40 mice suggested a possible metabolic alternation in axons. In support of alternative hypotheses, cuprizone induced significant intraneuronal amyloid deposition in young APP/PS1, but not in R1.40 mice, and it suggested the presence of PSEN deficiencies, may accelerate A{beta} deposition upon demyelination. In APP/PS1, mature OL is highly vulnerable to cuprizone with significant DNA double strand breaks (53BP1+) formation. Despite these major changes in myelin, OLs, and A{beta} immunoreactivity, no cognitive impairment or hippocampal pathology was detected in APP/PS1 mice after cuprizone treatment. Together, our data supports the hypothesis that myelin loss can be the cause, but not the consequence, of AD pathology. SIGNIFICANCE STATEMENTThe causal relationship between early myelin loss and the progression of Alzheimers disease remains unclear. Using two different AD mouse models, R1.40 and APP/PS1, our study supports the hypothesis that myelin abnormalities are upstream of amyloid production and deposition. We find that acute demyelination initiates intraneuronal amyloid deposition in the frontal cortex. Further, the loss of oligodendrocytes, coupled with the accelerated intraneuronal amyloid deposition, interferes with myelin tract diffusivity at a stage before any hippocampus pathology or cognitive impairments occur. We propose that myelin loss could be the cause, not the consequence, of amyloid pathology during the early stages of Alzheimers disease.