. Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1942-7. PubMed.


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  1. This is a very intriguing study by Fändrich, Friedrich, and colleagues modeling plaque formation in cultured cells following addition of exogenous Aβ. The methods used, including their EM, are excellent. Work such as this is important, while the continued reluctance to even consider the intracellular aspect of Aβ pathology is holding back the field. Leakage of Aβ from multivesicular bodies (MVBs) certainly is also consistent with what we observed by EM in brain. At the same time, the long trails of this Aβ are surprising. Cell culture model systems like the ones used in this paper have many advantages in studying the biological mechanisms of disease.

    I would add a few points to their discussion. Light and electron microscopy evidence supports that Aβ42 accumulation begins in neurons and particularly their distal neurites and synapses. The latter can help explain why one can have many plaques with little cell death. At the same time, our studies, as well as very nice work by D’Andrea and colleagues in human brain, and work by Vassar, Bayer, and others in AD transgenic mice, support that plaques also develop from neuron cell bodies. The current work additionally highlights the potential importance of glia in plaque formation. This study emphasizes Aβ internalization in plaque formation, although it is possible that not much Aβ internalization may be needed to upregulate an intracellular pool of Aβ that already is present in MVBs.

  2. These are very interesting studies of a topic that merits further investigation.

    It is noteworthy that earlier mRNA expression profile data support this notion. Briefly, Steve Ginsberg and colleagues (Ginsberg et al., 1999) followed up on two of our prior studies showing that RNA is sequestered in AD senile plaques (Ginsberg et al., 1997) and that Aβ is detected inside neurons (Wertkin et al., 1993). Thus, Ginsberg et al. analyzed the mRNA profile in single immunocytochemically identified plaques in sections of AD hippocampus. By using amplified RNA expression profiling, polymerase chain reaction, and in situ hybridization, Ginsberg et al. assessed the presence and abundance of 51 mRNAs that encode proteins implicated in the pathogenesis of AD. He compared the mRNAs in amyloid plaques with those in individual CA1 neurons and the surrounding neuropil of control subjects. Remarkably, Ginsberg et al. demonstrated that neuronal mRNAs predominated in amyloid plaques, thereby suggesting that these mRNAs are components of plaques and that these mRNAs may interact with Aβ released from dying neurons when plaques form at sites where neurons degenerate in the AD brain.

    View all comments by John Trojanowski
  3. Two things about this study puzzle me. I don’t understand why the uptake of Aβ peptides by macrophages in culture necessarily mimics the development of plaques in the brains of AD patients, or why it is even a good model system.

    The claim that internalized amyloid fibrils penetrate multivesicular membranes is a provocative one, but I question whether the immunostained, freeze-cleaved images that the authors provide are strong enough evidence to support this claim. To obtain these images, platinum-carbon replicas of cleaved cells were “washed” in SDS and then exposed sequentially to anti-Aβ antibodies and gold-labeled anti IGG. The assumption is made that the Aβ antigens in the cell adhere to the replicas, and remain in place during the washes and incubations. How much of the original antigenic material remains adherent to the replicas? Could some of it redistribute during the processing of the replica? The images of the vesicle membranes do not show obvious breaks, but these may be hard to recognize in these preparations. If such large clumps of amyloid fibrils do indeed stream out of multivesicular bodies, they should be easy to demonstrate by conventional thin-sectioning EM.

    View all comments by Vincent Marchesi
  4. Two papers published recently in PNAS (1,2) touch an issue close to our hearts: the nucleation of neuritic plaques in Alzheimer disease. The most important issue about the seeded polymerization hypothesis (3) at this time is the nature of the “bad” seed that could nucleate polymerization of soluble Aβ below the critical concentration. Where does the seed originate? How is it produced? Several years ago, we proposed that these seeds are generated inside specific populations of neurons, and that they accumulate at the neurite terminals. We described a culture system where CNS-derived neuronal cells (CAD) accumulate within their neurites oligomeric Aβ (4). We also proposed that these Aβ aggregates somehow become extracellular (e.g., by cell death, or through fusion of Aβ-containing compartments with the plasma membrane), and provided evidence that the aggregates are indeed externalized (5). In this way, they could readily nucleate the polymerization of the soluble Aβ present in the extracellular space. The question was where the Aβ that we detected inside the neurites comes from.

    Our data suggested that the intracellular Aβ aggregates reside in the late endosomes or autophagic vacuoles, since the oligomeric Aβ was detected in large vesicular structures that stain positive for Rab7, a marker for late endosomes and autophagic vacuoles. We also asked whether the neuritic Aβ aggregates could originate from the Aβ present in the culture medium that is taken up by cells via endocytosis. While we clearly showed that reuptake of Aβ via endocytosis does occur, the internalized Aβ accumulates in the cell body, not within the neurites (4), a result that is similar to what the featured papers now report (1,2).

    We concluded that the Aβ aggregates present in the cell body and those that accumulate in the neurites likely have a different origin. We still think that most plaques are nucleated from neuritic Aβ accumulations, not from cell body deposits. Certainly, it is possible that the endosomes in the cell body are later transported into the neurites, but this notion remains to be tested. Another interesting observation we made was that the neurites containing Aβ aggregates have fewer mitochondria, which cluster around the Aβ accumulations. Does this suggest a relationship between Aβ aggregation and disrupted/exhausted mitochondrial function? Future studies will tell. The CAD cell neuronal system proposed by us (4,6), as well as those used in the featured papers, SHSY5Y neuroblastoma cells (1,2), are ideal for pursuing such questions.

    Amazingly, the accumulation of Aβ aggregates occurs in CAD cell cultures without any addition of Aβ to the medium. All Aβ is produced from the endogenous APP that the CAD cells normally express. We know that CAD cells actively produce Aβ, which polymerizes within the cells to form low and high oligomers, detectable with anti-Aβ and anti-oligomer antibodies. A detailed description of our view on how these neuritic Aβ accumulations could nucleate plaques in AD is given elsewhere (4,5).

    Those interested could also take a look at our two SWAN-style hypotheses on the ARF website (6,7). To conclude, we have to sadly agree with Gunnar Gouras, who mentioned in his comment from 22 January 2010, the reluctance of many investigators to even consider the intracellular aspect of Aβ pathology. Researchers should definitely pay closer attention to the intracellular Aβ aggregates, because these could be key to the pathogenesis of AD.

    See also:

    Muresan, Z. and V. Muresan, CAD cells are a useful model for studies of APP cell biology and Alzheimer’s disease pathology, including accumulation of Aβ within neurites. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum. 2009.

    Muresan, Z. and V. Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum.

    View all comments by Virgil Muresan