Since Alois Alzheimer’s first descriptions of senile plaques, we have known that they are associated with dementia. But are they detrimental? Are these amyloid-β (Aβ) deposits perpetrators or innocent bystanders? Nearly a century later, a verdict is still not in. Now that we know neurodegeneration can occur without plaque formation, and that intracellular Aβ (see ARF related news story) and small oligomers of the peptide may cause their fair share of toxicity (see ARF related news story), is it time to acquit the larger Aβ deposits? Maybe not—a report in the October 10 Nature Neuroscience online bolsters the case against plaques. The authors provide new photographic evidence implicating Aβ deposits in neuronal damage.
Wen-Biao Gan and colleagues at New York University School of Medicine used two-photon fluorescent imaging to examine neuronal architecture in the vicinity of plaques. First author Julie Tsai and coauthors found that in brain tissue from transgenic mice expressing mutant human amyloid-β precursor protein, neurons that passed through amyloid plaques were damaged. On average, dendrites in plaques had lost nearly 50 percent of their spines, the pinhead-like structures that facilitate communication between dendrites and other neurons. Axons that passed through, or skirted, plaques were also dramatically affected, becoming either constricted, or ballooning out like varicose veins. The danger zone appeared to extend to 15 micrometers from the plaque surface. Within this sphere, 90 percent of axons showed some degree of varicosity. Axons outside this boundary appeared normal.
Tsai and colleagues were able to extend these observations to living tissue. Using a recently developed transcranial microscope, they peered through the skulls of transgenic mice and were able to image amyloid deposits, and their surrounding neurons, for weeks at a time. Tsai and colleagues found that both axons and dendrites were gradually eliminated if they were within 15 micrometers of a plaque. In fact, over 36 percent of them were eliminated during a period of 4-5 weeks. The results indicate that neurodegeneration occurs after, or at least concomitantly with, plaque formation.
A picture paints a thousand words
These two-photon fluorescent images, taken transcranially from live mice reveal that neurites near amyloid deposits undergo gross morphological changes, and eventually disappear. In these images, taken over a period of eight days, neurons stained with the lipophilic dye DiI appear green, while amyloid plaques appear red (scale bar is 10 micrometers). [Image courtesy of Wen-Biao Gan and Nature Neuroscience]
This work supports similar findings that were published in the late nineties using fixed tissue sections from transgenic animals (see, for example, Phinney et al., 1999 and Knowles et al., 1999). “Our results suggest that the accumulation of fibrillar amyloid causes not only local structural disruption of synapses but also eventual neurite breakage, indicating that amyloid deposition is far more detrimental to the brain than previously thought,” write the authors, though they concede that the damaging factor may not be fibrillar Aβ alone, but could include small Aβ peptides.—Tom Fagan
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- Phinney AL, Deller T, Stalder M, Calhoun ME, Frotscher M, Sommer B, Staufenbiel M, Jucker M. Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice. J Neurosci. 1999 Oct 1;19(19):8552-9. PubMed.
- Knowles RB, Wyart C, Buldyrev SV, Cruz L, Urbanc B, Hasselmo ME, Stanley HE, Hyman BT. Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5274-9. PubMed.
No Available Further Reading
- Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004 Nov;7(11):1181-3. PubMed.