Abstract
Alzheimer’s disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 235-256 |
| Number of pages | 22 |
| Journal | Acta Neuropathologica |
| Volume | 132 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 1 2016 |
Funding
The authors would like to thank Lawrence Rajendran and Patrick Keller for the generous gift of the anti-sAPPβ Swedish antibody (ANJJ), Virginia Lee for the anti-APP antibody (Karen), Lisa McConlogue for anti-Aβ antibody (3D6), and Lester Binder for the anti-βIII tubulin antibody (TuJ1). We would also like to thank Lawrence Rajendran for thoughtful comments on the manuscript and Eileen H. Bigio in the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University (funded by NIH R01 AG13854) for human post-mortem brain tissue. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Spinning disk confocal microscopy was performed on an Andor XDI Revolution microscope, purchased through the support of NCRR 1S10 RR031680-01. Multi-photon microscopy was performed on a Nikon A1R multi-photon microscope, acquired through the support of NIH 1S10OD010398-01. This work was supported by NIH R01 AG030142, the Cure Alzheimer’s Fund, and the Baila Foundation to RV, NIH R01 AG019070 and the Cure Alzheimer’s Fund to GT, BrightFocus Foundation to VB-P, and NIH T32-070715 to PCK.
Keywords
- 5XFAD mice
- Alzheimer’s disease
- Amyloid
- Axonal transport
- Aβ
- BACE1
- Cathepsin D
- Dystrophic neurite
- Microtubule
- Tubulin
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience