Pathologically, multiple sclerosis (MS) can be identified by the presence of diffuse, discrete demyelinated areas, called plaques. Demyelination is a major feature of MS and therefore, an approach to the management of MS involves an increase in remyelination of axons, resulting in clinical improvement. Peroxisome proliferator-activated receptor β or δ (PPARβ) being highly expressed in the CNS participates in many brain functions including myelination. Being a nuclear hormone receptor, PPARβ needs ligand(s) for its activation and nuclear translocation. Therefore, identification of new nontoxic ligand of PPARβ would be very important for promoting remyelination. The β-hydroxy β-methylbutyrate (HMB) is available in local GNC stores as a muscle-building supplement in human. It is a physiological molecule that is produced in human through the metabolism of L-leucine. HMB is known to increase exercise-induced gains in muscle size and muscle strength and improve exercise performance. Our preliminary results show that HMB may bind and activate PPARβ and stimulate the maturation of oligodendroglial progenitor cells (OPCs) to oligodendrocytes (OL), myelin-producing cells in the CNS. Therefore, here, we will test an exciting hypothesis that HMB binds to the ligand- binding domain of PPARβ and that HMB and its precursor L-leucine promote maturation of OPCs and stimulate remyelination in animal models (cuprizone and experimental allergic encephalomyelitis) of CNS demyelination via PPARβ. Administrative supplement: One of the pathologic hallmarks of Alzheimer’s disease (AD) is the presence of neurofibrillary tangles containing aggregated tau. Effective reduction of aggregated tau from the brain parenchyma is expected to reduce the disease process of AD, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and other tauopathies. Despite intense investigations, no effective therapy is available to reduce tauopathy. Since microglial activation plays an important role in different neurodegenerative disorders including tauopathy, we examined the effect of muscle-building supplement HMB on microglial activation and found that HMB is capable of inhibiting tau fibril-mediated activation of microglia in culture as well as suppressing glial inflammation in vivo in the hippocampus of P301S Tau or PS19 mouse model of AD. Therefore, this administrative supplement in response to NOT-AG-21-018 has been devoted to test an exciting hypothesis that oral administration of HMB and its precursor L- leucine inhibits microglial inflammation to lower tauopathy and improve cognitive functions in PS19 mouse model of AD. A positive outcome of this administrative supplement will enhance the possibility of inhibiting microglial activation, lowering tauopathy and improving cognitive functions in patients with AD, PSP, FTD, and other tauopathies with muscle-building supplement HMB and a simple non-toxic amino acid L-leucine as primary or adjunct therapy.