The Journal of Neuroscience, December 7, 2005, ():
-Secretase-Cleaved Amyloid Precursor Protein Accumulates at Actin Inclusions Induced in Neurons by Stress or Amyloid : A Feedforward Mechanism for Alzheimer's Disease
J. Neurosci. Maloney et al.
25: 11313
Supplemental data
Files in this Data Supplement:
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Supplementary Figure S1: Preparation of dissociated cultures enriched for CA1 or CA3 neurons. (a-c) Left and right hippocampal slices from brain showing the pyramidal cell layer of the hippocampus taken on a Nikon diaphot microscope with a 40x objective. (d-f) Observations of the hippocampi from a dissection microscope used for making the bisections of the CA1 and CA3 regions. Scale bars = 100 μm. CA1 = Cornu Amonis region 1, CA3 = Cornu Amonis region 3, DG = Dentate Gyrus, f = fimbria. Black arrow points to hippocampal fissure.
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Supplementary Figure S2: AFM and EM images of Aβ aggregates in vitro and amyloid plaque in human brain. (a) Negative stained EM photomicrograph of an amyloid plaque from human Alzheimer diseased brain (scale bar = 2 μm). (b-d) EM images (boxes are 2x2 μm). (e-i) AFM images (boxes are 2x2 μm). (h, i) Supernatant and pellet fractions from a fibril/insoluble aggregate preparation following centrifugation at 20,000xg for 15min. (j) Magnification of a 2x2 μm section from the amyloid plaque (a).
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Supplementary Figure S3: Aβ aggregates are visible by phase microscopy. E18 rat hippocampal neurons (6div) were either untreated (a) or treated with: (b) 1 μM LMW, (c) 1 μM large oligomers, (d) 1 μM fibrils/insoluble aggregates, (e) 1.3 μM fibril supernatant, (f) 0.65 μM insoluble aggregate pellet. Arrows indicate peptide aggregates.
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Supplementary Figure S4: Distribution of Aβ aggregates in cell culture. E18 rat hippocampal neurons (6 div) were either untreated or treated with variously prepared Aβ peptides as labeled. Culture medium was evaporated and neurons and Aβ peptides stained as labeled. Abbreviations as in Figure 1.
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Supplementary Figure S5: Vesicles containing BACE and PS1 accumulate at ADF/cofilin-containing rods in neurites. Untreated E18 rat hippocampal neurons and 20 min ATP-depleted neurons that had undergone a 24 h recovery were fixed 7 div and immunostained as labeled.
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Supplementary Figure S6. Hypothetical model for a convergent feed-forward mechanism of plaque formation and neurodegeneration in familial and sporadic Alzheimer’s disease. Inherited mutations, as in FAD, lead to increased Aβ that can induce rod formation in a sensitive population of neurons. Other forms of neuronal stress, such as ischemic injury, excitotoxicity or oxidative stress induce rod formation and may lead to sporadic AD. Disruption of APP-, BACE- and PS1-containing vesicles by rods may lead to locally elevated Aβ production in neurites. Aβ can either be sequestered into insoluble plaques or soluble Aβ can induce further rod formation in the surrounding neuropil exacerbating the neurodegenerative cycle.
