Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes

Area of Science:

• Neuroscience
• Metabolic pathways
• Cellular biology

Background:

• Altered energy metabolism is a key feature of Alzheimer's disease (AD), particularly in astrocytes, which maintain brain homeostasis.
• While global metabolic changes in AD are studied, the specific interplay of metabolic processes within astrocytes remains unclear.
• Amyloid-beta and its precursor protein processing are implicated in AD pathogenesis.

Purpose of the Study:

• To investigate the impact of familial AD on astrocyte metabolism.
• To compare astrocyte metabolic changes in familial AD with those induced by acute amyloid-beta exposure.
• To identify potential early pathological hallmarks and therapeutic targets in AD.

Main Methods:

• Astrocytes were differentiated from induced pluripotent stem cells (iPSCs) derived from familial AD patients and controls.
• Metabolic profiles, including glucose and glutamate uptake and lactate release, were analyzed.
• Changes in major metabolic pathways, oxidative and glycolytic metabolism, and evidence of gliosis were assessed.

Main Results:

• Familial AD astrocytes exhibited significant alterations in glucose uptake, glutamate uptake, and lactate release compared to controls.
• Increased oxidative and glycolytic metabolism was observed in familial AD astrocytes, exceeding effects of acute amyloid-beta exposure.
• Dysregulation of glutamate, purine, and arginine metabolism, along with the citric acid cycle, was identified.
• Evidence of gliosis was found in familial AD astrocytes, suggesting a pathological hallmark.

Conclusions:

• Chronic metabolic alterations occur very early in familial AD astrocytes, preceding or independent of acute amyloid-beta effects.
• These early metabolic changes in astrocytes are potential risk factors for early-onset AD progression.
• Findings highlight astrocytes' role in AD pathogenesis and suggest potential diagnostic and therapeutic targets for both early and late-onset dementia.