Abstract
Abnormal energy homeostasis in Alzheimer’s Disease (AD) is associated with synaptic dysfunction and
neurodegeneration. Emerging data generated using multiple systems biology approaches and meta-analysis
in AD patients identified an AMP-protein kinase (AMPK) integrated signaling network that operates down
stream of mitochondrial energy production and could provide neuroprotection in AD. We show that partial
inhibition of mitochondrial complex I (MCI) improves glucose uptake and utilization, dendritic spine maturation,
long-term potentiation, synaptic activity, cognitive function, and reduces Aß and pTau accumulation, oxidative
stress and inflammation resulting in neuroprotection in pre- and symptomatic preclinical mouse models of AD
and aging. These studies suggest that novel strategies to alter mitochondrial energy homeostasis may have
profound translational therapeutic potential for AD. Using multiple biochemistry, computational and systems
biology approaches, and extensive in vivo translational studies, we developed small molecules that bind next
to the flavin mononucleotide redox center of MCI mildly inhibiting its activity. The molecular mechanism of MCI
inhibitors impinges on pathways induced by caloric restriction and exercise including activation of AMPK;
increased resistance to oxidative stress; enhanced mitochondrial biogenesis, energetics, dynamics and
function; reduction of glycogen synthase kinase 3ß activity; increased levels of brain-derived neurotrophic
factor (BDNF) and synaptic proteins in vivo; a reduction in levels of Aß and pTau and inflammation ultimately
blocking neurodegeneration in AD mice. We have confirmed these effects in a range of systems (primary
mouse neurons, multiple mouse models of familial AD, wild-type mice fed with a high fat diet, chronologically
aged mice, mitochondria isolated from mouse and human brain, human lymphocytes, fibroblasts and neuronal
cells differentiated from human iPSCs), supporting the high translational potential of this approach. The
advantages of our molecules include the ability to penetrate the blood brain barrier, low toxicity, in vivo
efficacy, and the known molecular target. Based on the target validation and the identification of the molecular
mechanism, we developed multiple in vitro and in vivo assays that were used for structure-activity relationship
(SAR) studies resulting in the development of a robust Discovery Funnel and arrays of novel series of
proprietary compounds MCI inhibitors with promising drug-like properties (US patent granted). We propose to
advance our small molecule therapeutics to the clinic by entering the BPN at the Discovery stage where, with
the team of the BPN Consultants and CROs, we will progress toward the identification of preclinical and
development candidates, and to the submission of the IND application in preparation for a Phase I Clinical
Trial.