An article in the February 24 Nature Neuroscience online suggests that amyloid-β (Aβ), the peptide responsible for the intercellular plaques that appear in the brains of Alzheimer's patients, can freely diffuse through neural tissue, and that it plays a major role in the pathogenesis of the disease.
Mathias Jucker, University of Basel, Switzerland, with colleagues in the USA and Belgium, grafted hippocampal or cortical tissue from normal mice into the hippocampus or cortex of transgenic animals expressing mutant forms of human AβPP. When first author Melanie Meyer-Luehmann and colleagues examined the mice three months later, they found amyloid plaques in the graft tissue. These plaques could only have formed with Aβ from the host, indicating that the peptide can freely diffuse through the brain. In contrast, when the authors placed mutant AβPP-expressing grafts into wild-type hosts, no plaques appeared in the grafts even after 20 months, a duration that would normally bring considerable numbers of plaques to transgenic AβPP animals. This result suggests that Aβ can diffuse out of the grafts, leaving insufficient peptide to precipitate plaque formation.
In the latter instance, the authors went to considerable lengths to prove that the graft tissue did indeed produce Aβ. The grafts appeared well integrated, healthy, and viable, and graft tissue samples had peptide levels comparable to those found in intact animals. The authors asked whether the lack of deposits might be the result of the host immune system soaking up graft-derived Aβ, but host anti-Aβ antibodies were no higher than in control animals.
One interesting finding was that when normal grafts were placed in transgenic hosts, Aβ deposits were more abundant in the graft than in the surrounding host tissue. Furthermore, the border between graft and host tissue had the highest density of deposits. These results suggest that inflammation around the site of the graft contributed to Aβ deposition. However, when the authors tested this hypothesis by inducing inflammation in the absence of graft tissue, they did not observe any induction of deposits.
"This paper is really fascinating," commented Dave Holtzman from Washington University in St. Louis, Missouri. "It clearly demonstrates the importance of 'clearance' of Aβ from the extracellular space, and that clearance is a key mechanism that determines whether Aβ will deposit. It may be that transport across the BBB or local transport along the interstitial fluid drainage pathway, or both, are critical pathways that determine Aβ clearance."
The authors point out that their results suggest that intracellular Aβ is not a prerequisite for extracellular amyloid deposition. The paper also addresses the longstanding question of whether extracellular Aβ is toxic to neurons. Though this has been studied extensively and shown to be the case in vitro (see, for example, ARF related news story), it has proven more difficult to determine in vivo. Meyer-Luehmann show that when normal grafts are placed in AβPP transgenic mice, neurons in the vicinity of plaques have multiple signs of degeneration, including the presence of structures testing positive for hyperphosphorylated tau, which is found in the neurofibrillary tangles commonly found in AD. This finding supports other recent work implicating plaques in neurodegeneration (see ARF related news story).—Tom Fagan
- Hone E, Martins IJ, Fonte J, Martins RN. Apolipoprotein E influences amyloid-beta clearance from the murine periphery. J Alzheimers Dis. 2003 Feb;5(1):1-8. PubMed.
- Meyer-Luehmann M, Stalder M, Herzig MC, Kaeser SA, Kohler E, Pfeifer M, Boncristiano S, Mathews PM, Mercken M, Abramowski D, Staufenbiel M, Jucker M. Extracellular amyloid formation and associated pathology in neural grafts. Nat Neurosci. 2003 Apr;6(4):370-7. PubMed.