It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of neural cells to development of microgliosis and clinical neuropathology, the constitutive mouse model was compared to a neural selective mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive mice, microglia in mice only become mildly inflammatory at end stage of disease. microglia are primed and acquire a chronic and strong inflammatory state in mice whereas microglia in mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in mice and strongly indicates a cell-autonomous role of MFP2 in microglia.