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 (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.
RESULTS
NiMA is inhibited in APPSAA 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 APPSAA mice.
DISCUSSION
NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA 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 (APPSAA/+) mice.
NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice.
Pharmacological interventions can rescue AD-related NiMA disruption in vivo.
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This post is Copyright: Andrés Norambuena,
Vijay Kumar Sagar,
Zhuoying Wang,
Prakash Raut,
Ziang Feng,
Horst Wallrabe,
Evelyn Pardo,
Taylor Kim,
Shagufta Rehman Alam,
Song Hu,
Ammasi Periasamy,
George S. Bloom | August 22, 2024