Glucose dysregulation in pre-clinical Alzheimer’s disease

age-related dementia and neurodegenerative disease [1]. Despite the impact on public health and the economic burden in ageing societies, no disease-modifying therapies exist, and AD remains incurable. AD pathology can begin long before the appearance of outward clinical symptoms [1-3], and the well-publicised failures of clinical trials targeting symptomatic AD highlight the need for pre-symptomatic biomarkers and therapies. Although theories abound for the underlying mechanisms of neurodegeneration in AD, studies are commonly performed in post-mortem AD brains or in models where pathology is already apparent. Elucidation of pathology initiation and progression at the molecular level requires the use of appropriate presymptomatic AD models and innovative analytical approaches. Using experimental and computational techniques, we recently demonstrated an impairment of glucose metabolism in primary neurons from a double transgenic mouse model of AD (PS2N141IAPPswe/ B6.152H), and showed that this impairment affects NADH-mediated mitochondrial bioenergetics while mitochondrial integrity remains intact [4]. Interestingly, glucose hypo-metabolism occurs in clinical AD and correlates with the severity of cognitive decline [1, 5]. Moreover, glucose metabolism abnormalities can be measured before the onset of cognitive impairment, may begin years or even decades before the onset of clinical symptoms, and are reliable indicators of disease progression [1, 3]. Although 18FDG-PET imaging studies in AD animal models are thus far inconsistent [6], our study demonstrated that glucose metabolism defects are detectable in vitro prior to the appearance of Amyloid beta (Aβ) pathology or behavioural phenotypes, and highlighted the utility of an interdisciplinary approach [4]. The consequences of glucose hypo-metabolism are manifold, most of which have been reported in AD. Reduced cytosolic NADH production and carbon fluxes to mitochondria contribute to impaired mitochondrial function and potential bioenergetic crisis involving reduced ATP production, increased ROS levels and oxidative stress, calcium de-regulation, synaptic activity disruption, and neurodegeneration. The pentose phosphate pathway, other biosynthetic pathways, glycosylation, and mitochondrial movement can also be affected. Even in the absence of overt bioenergetic crisis, Editorial