Background: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease characterized by progressive demyelination of the central nervous system. It is caused by mutations in ABCD1 gene that encode peroxisomal membrane transporter protein, adrenoleukodystrophy protein (ALDP). X-ALD exhibits remarkable phenotypic variability ranging from fatal cerebral adrenoleukodystrophy (cALD) to mild adrenomyeloneurpathy (AMN) with no phenotype-genotype correlation. The mouse model of X-ALD (Abcd1-KO) does not reproduce the human severe phenotypic (cALD) and only exhibits phenotype resembling AMN. We recently reported a novel loss of AMP-activated protein kinase α1 (AMPKα1) in cALD patient-derived cells and postmortem brain tissue. Objective: We hypothesized that loss of AMPKα1 may be a physiopathogenic factor in progression to cALD. To test this hypothesis, we generated a novel Abcd1 and AMPKα1 double knock-out mice (D-KO). Results: Abcd1-KO female (Abcd1-KO) and AMPKα1-KO male mice were crossbred to generate dual-heterozygote-deficient progeny (F1). The F1 progeny were crossbred, to obtain double knockout F2 progeny, which were homozygous for Abcd1/AMPKα1 deficiency (D-KO). Gene expression and histological studies provide evidence of significantly higher proinflammatory genes expression and loss of myelin in the brain and spinal cord of the D-KO mice. Mitochondrial dysfunction was measured as oxygen consumption rate (OCR) in mice brain-isolated mitochondria. Mitochondrial OCR was significantly reduced in the isolated brain mitochondria of D-KO mice compared to wild type and Abcd1-KO. Conclusions: The novel D-KO mice, represents the inflammatory severe phenotype of human X-linked adrenoleukodystrophy disease. This novel mouse model will be useful in deciphering the mechanistic underpinnings of disease progression in cALD.