Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease

Abstract

Introduction: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo.

Methods: Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APP^SAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.

Results: NiMA is inhibited in APP^SAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP^SAA mice.

Discussion: NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APP^SAA mice, and may represent an early stage in human AD.

Highlights: Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APP^SAA/+) mice. NiMA is disrupted long before learning and memory deficits in APP^SAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.

Keywords: amino acids; brain metabolism; insulin; mammalian target of rapamycin; tau.