Parkin prevents cortical atrophy and Aβ-induced alterations of brain metabolism: 13C NMR and magnetic resonance imaging studies in AD models

Alzheimer’s disease (AD) is a neurodegenerative aging disorder characterized by extracellular Aβ plaques and intraneuronal neurofibrillary tangles. We conducted longitudinal studies to examine the effects of Aβ on brain amino acid metabolism in lentiviral Aβ1–42 gene transfer animals and transgenic AD mice. We also performed lentiviral parkin gene delivery to determine the effects of Aβ clearance in AD models. Aβ1–42 activated mTOR signaling, and increased 4E-BP phosphorylation. Aβ1–42 increased the synthesis of glutamate and aspartate, but not glutamine, leucine and isoleucine, but an increase in leucine and isoleucine levels was concurrent with diminution of neurotransmitters. Additionally, Aβ1–42 attenuated mitochondrial tricarboxylic acid (TCA) cycle activity and decreased synthesis of its by-products. Glutamate levels increased prior to lactate accumulation, suggesting oxidative stress. Importantly, parkin reversed the effects of Aβ1–42 on amino acid levels, prevented TCA cycle impairment and protected against glutamate toxicity. Cortical atrophy was observed in aged 3xTg-AD mice, while parkin expression was associated with reduced atrophy. Similarly, Aβ1–42 resulted in significant cell loss, pronounced astrogliosis and cortical atrophy and parkin reduced astrogliosis and reversed Aβ1–42 effects on cell loss and cortical atrophy. Taken together these data suggest that parkin prevents amyloid-induced alteration of brain metabolism and may be used as a therapeutic target to limit neuronal loss in AD.

► Aβ1–42 increases glutamate and aspartate, but not glutamine levels.
► Glutamate levels increased prior to lactate accumulation.
► Aβ1–42 attenuated mitochondrial TCA cycle and parkin reversed these effects.
► Parkin protected against Aβ1–42 effects on amino acid and glutamate toxicity.
► Parkin reduced astrogliosis and reversed cell loss and cortical atrophy.