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 Aβ(1-42) gene transfer animals and transgenic AD mice. We also performed lentiviral parkin gene delivery to determine the effects of Aβ clearance in AD models. Aβ(1-42) activated mTOR signaling, and increased 4E-BP phosphorylation. Aβ(1-42) 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, Aβ(1-42) 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 Aβ(1-42) 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, Aβ(1-42) resulted in significant cell loss, pronounced astrogliosis and cortical atrophy and parkin reduced astrogliosis and reversed Aβ(1-42) 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.