17 Oct 2003

The chemokine receptor CCR1 might be an early and specific marker of Alzheimer's disease, researchers suggest in the November issue of Annals of Neurology, now available online.

Meredith Halks-Miller and colleagues at Berlex Biosciences, Richmond, California, had previously reported the presence of CCR1 in a handful of AD cases. Together with collaborators at Mt. Sinai Medical Center, New York; Schering AG, Berlin, Germany; and the University of Pittsburgh, Halks-Miller has expanded these observations by examining autopsy samples from patients who had either AD (n=40), one of several other neurodegenerative diseases (n=29), or no neurodegenerative disease (n=10). Using antibodies against CCR1, the authors found that the receptor was expressed in the frontal cortex and hippocampus in AD samples, particularly in dystrophic neurites and plaques. In normal brain tissue, only the ependyma was found to react with the antibodies, and this was minimal.

Halks-Miller et al. report a direct correlation among the clinical dementia rating score (CDR), the number of Aβ42 plaques, and the number of plaques that tested positive for CCR1. Interestingly, samples from people who had low CDR scores (0.5 or 1.0) when they died already had a three- to fivefold increase in CCR1, even while the numbers of Aβ40-positive plaques were few. As plaques containing Aβ40 are not usually apparent until the later stages of the disease, this finding would make CCR1 an "earlier marker of AD pathological state than Aβ40," according to the authors. The scientists did not detect CCR1-positive structures in brain samples taken from victims of other neurodegenerative diseases, including Parkinson's and Lewy body dementia, unless there was also evidence of amyloid plaques. This suggests that CCR1 is a somewhat specific marker for Aβ42.

Why CCR1 expression should accompany Aβ deposition is uncertain, but the authors suggest that proinflammatory signals, perhaps induced by the amyloid peptides, may be responsible. In this regard, it is worth noting that Richard Ransohoff and colleagues reported two years ago that CCR1-positive phagocytes accumulate in the CNS of patients with multiple sclerosis (see Trebst et al., 2001).

"This is a fascinating study for several reasons," comments Ransohoff, from the Cleveland Clinic Foundation. "It is obviously good to have a specific early marker for AD; it has potential therapeutic applications, and it adds weight to the idea that CCR1 expression on neurons might be physiologically important." With respect to the latter, he points out that Faye Silverstein and colleagues reported this year that CCR1 is expressed in cerebellar neurons during early development (see Cowell and Silverstein, 2003).

Drugs targeting CCR1 are in early clinical trials for multiple sclerosis (Berlex) and rheumatoid arthritis (Pfizer), though as Ransohoff points out, these may need to be modified to penetrate the blood-brain barrier.—Tom Fagan

Comments

1. • David Holtzman
     Washington University
   • Posted: 21 Oct 2003

   This paper shows that immunostaining for CCR1 is increased in AD brains and tends to increase as the clinical stage of dementia is more severe. The staining appears to be relatively specific for brains that have Aβ deposition. This marker, if it can be measured in a biological fluid, would be interesting to assess to determine if similar changes can be
   detected in living individuals. This has not yet been studied.

   One point the authors make is that CCR1 increases as dementia increases, and that more CCR1 staining is present as Aβ40 staining in the brain increases. Further, they state that Aβ40 staining is only seen much in clinical dementia rating (CDR) 2 brains and greater.

   I wonder whether the Aβ40 antibody and conditions being used are very sensitive That is because it has previously been found that Aβ40 accumulates as neuritic plaques and CAA accumulate, and is present with lots of plaques at all stages of AD, even preclinical AD, at CDR0.5 and CDR1.

   View all comments by David Holtzman
2. • Manuel Menendez-Gonzalez
     Hospital Universitario Central de Asturias
   • Posted: 21 Oct 2003

   I agree with thinking this is a fascinating study specially due to the knowledgment it provides about AD physiopathology and putative treatments, but I don´t think this is a useful test for the daily clinical management of patients with possible AD because it´s very invasive. I´m very interested in CSF biomarkers and I think that beta amyloid and phosphotau could be a interesting test to be used in diagnosis of patients with MCI.

   View all comments by Manuel Menendez-Gonzalez

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Trebst C, Sørensen TL, Kivisäkk P, Cathcart MK, Hesselgesser J, Horuk R, Sellebjerg F, Lassmann H, Ransohoff RM. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am J Pathol. 2001 Nov;159(5):1701-10. PubMed.
2. Cowell RM, Silverstein FS. Developmental changes in the expression of chemokine receptor CCR1 in the rat cerebellum. J Comp Neurol. 2003 Feb 24;457(1):7-23. PubMed.

Further Reading

No Available Further Reading