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

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) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.

RESULTS

NiMA is inhibited in APP 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 mice.

DISCUSSION

NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APP 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) mice. NiMA is disrupted long before learning and memory deficits in APP mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.