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Aβ42 oligomers impair the bioenergetic activity in hippocampal synaptosomes derived from APP-KO mice

Benedikt Beckert1, Amparo Acker-Palmer1,2, Walter Volknandt1,3

  • 1Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt/Main, Germany.

Biological Chemistry
|January 17, 2018
PubMed

Insights

Oligomeric amyloid beta 42 (Aβ42) peptide immediately impairs mitochondrial function and membrane potential in hippocampal synaptosomes. Soluble amyloid precursor protein alpha (sAPPα) had no effect, highlighting Aβ42

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Amyloid beta peptide 42 (Aβ42) is implicated in neurodegenerative diseases.
  • The precise mechanisms by which Aβ42 affects neuronal bioenergetics remain incompletely understood.
  • Amyloid precursor protein (APP) knockout (APP-KO) mice offer a model to study Aβ42's direct effects.

Purpose of the Study:

  • To investigate the immediate impact of different amyloid beta 42 (Aβ42) forms on hippocampal synaptosome bioenergetic activity.
  • To assess the influence of soluble amyloid precursor protein alpha (sAPPα) on mitochondrial function.
  • To validate APP-KO mouse hippocampal synaptosomes as a model for studying Aβ42-induced mitochondrial dysfunction.

Main Methods:

  • Utilized hippocampal synaptosomes isolated from amyloid precursor protein (APP)-deleted mice.
  • Administered oligomeric, fibrillar, and scrambled amyloid beta peptide 42 (Aβ42) to synaptosomes.
  • Measured mitochondrial activity and mitochondrial membrane potential (MMP).
  • Assessed the effects of soluble amyloid precursor protein alpha (sAPPα) at varying concentrations.

Main Results:

  • Oligomeric Aβ42 significantly decreased mitochondrial activity and MMP within 30 minutes.
  • Fibrillar or scrambled Aβ42 peptides did not affect mitochondrial function.
  • APP-KO synaptosomes from older mice showed exacerbated bioenergetic impairment upon Aβ42 exposure.
  • sAPPα did not alter mitochondrial metabolic activity in synaptosomes from young or old APP-KO mice.
  • Extracellular Aβ42 was observed to be taken up into synaptosomes, leading to immediate mitochondrial attenuation.

Conclusions:

  • Oligomeric Aβ42 directly and rapidly impairs mitochondrial function in hippocampal synaptosomes.
  • The oligomeric state of Aβ42 is critical for its inhibitory effect on mitochondrial activity.
  • APP-KO mouse hippocampal synaptosomes are a suitable model for studying Aβ42's impact on bioenergetics.
  • Extracellular Aβ42 uptake leads to immediate attenuation of mitochondrial activity within synaptosomes.
Keywords:
amyloid precursor proteinamyloid-βbioenergetic activityhippocampal synaptosomesmitochondrial membrane potential

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