Amyloid-β plaques disrupt axon initial segments.
Amyloid-β (Aβ) plaques are one of the central pathologies of Alzheimer's disease (AD). Plaque formation in animal models of AD coincides with the appearance of synaptic abnormalities, aberrant neuronal excitability, and cognitive decline. Aβ plaques may disrupt neuronal excitability since they have been proposed to be synaptotoxic, to induce axonal varicosities and neurite breakage, and to significantly decrease spine density. Axon initial segments (AIS) also regulate neuronal excitability and help maintain neuronal polarity. Despite these essential functions, the effects of plaques on AIS structure have not been fully determined. Using a mouse AD model, we measured a significant decrease in the density of AIS up to 75μm away from the center of fibrillar, thioflavin-labeled plaques. The reduction was observed in animals with both moderate and severe plaque loads, and was associated with increased densities of microglia near the plaques. Furthermore, animals with severe plaque loads had significantly reduced AIS lengths adjacent to Aβ plaques. These results suggest the local environment surrounding Aβ plaques may be harmful to the AIS. We propose that AIS loss is a previously unappreciated consequence of AD that could significantly impact brain function.



This paper demonstrates that neurons near Aβ plaques have disrupted axon initial segments. Loss or disruption of AIS is predicted to have detrimental consequences for brain function.
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Miguel A
MA
Marin
Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
Jokubus
J
Ziburkus
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Joanna
J
Jankowsky
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: rasband@bcm.edu.
Matthew N
MN
Rasband
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000071040:Axon Initial Segment / Q000473:pathology* / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology*
D016564:Amyloid beta-Protein Precursor; D015815:Cell Adhesion Molecules; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1
Alzheimer's; Axon; Degeneration; Ion channel