Nikolic WV, Hou H, Town T, Zhu Y, Giunta B, Sanberg CD, Zeng J, Luo D, Ehrhart J, Mori T, Sanberg PR, Tan J. Peripherally administered human umbilical cord blood cells reduce parenchymal and vascular beta-amyloid deposits in Alzheimer mice. Stem Cells Dev. 2008 Jun;17(3):423-39. PubMed.
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Jikei University School of Medicine
Comment by Mark A. Smith, Rudy J. Castellani, Hyoung-gon Lee, Akihiko Nunomura, Xiongwei Zhu, and George Perry
Amyloid-β: The Beginning of the End and the End of the Beginning
The paper by Head and colleagues (2008) should serve as a major warning for those hoping that removing amyloid will be effective in the treatment of Alzheimer disease (AD) or age-related cognitive impairment. So far, aside from transgenic mice engineered to overproduce amyloid, the record for amyloid immunotherapy has been one of abject failure: 1) trial suspension (human) and 2) no improvement (dogs). At minimum, these studies indicate that our current mouse models of AD are inadequate and, being amyloidocentric, naturally respond to amyloidocentric therapies. By contrast, rather than being driven by a transgene, the amyloid in aging or AD is there for a physiological or pathological reason (Nunomura et al., 2001), and removal of amyloid will not remove these precipitating factors. Moreover, we suspect that the production of amyloid, in response to a primary disease etiology, may serve a beneficial function such that the removal of amyloid would be detrimental and exacerbate any underlying pathological processes (Perry et al., 2000; Rottkamp et al., 2002; Smith et al., 2002; Castellani et al., 2006; Lee et al., 2006a). We previously noted the existence of amyloid spin doctors (Castellani et al., 2007) and wonder whether the ever-increasing inconsistencies in the amyloid hypothesis (Lee et al., 2006b), together with recent therapeutic failures, will finally lead to the realization that it is time to stop spinning. Perhaps the time has come for this to be the beginning of the end for amyloid and the end of the beginning in our quest to understand and treat this disease.
See also:
Castellani R, Lee HG, Perry G, Smith MA, Zhu X (2007) ARF Comment: Amyloid spin doctors.
References:
Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol. 2006 Jun;111(6):503-9. PubMed.
Head E, Pop V, Vasilevko V, Hill M, Saing T, Sarsoza F, Nistor M, Christie LA, Milton S, Glabe C, Barrett E, Cribbs D. A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta. J Neurosci. 2008 Apr 2;28(14):3555-66. PubMed.
Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Amyloid-beta vaccination: testing the amyloid hypothesis?: heads we win, tails you lose!. Am J Pathol. 2006 Sep;169(3):738-9. PubMed.
Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Amyloid beta: the alternate hypothesis. Curr Alzheimer Res. 2006 Feb;3(1):75-80. PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.
Perry G, Nunomura A, Raina AK, Smith MA. Amyloid-beta junkies. Lancet. 2000 Feb 26;355(9205):757. PubMed.
Rottkamp CA, Atwood CS, Joseph JA, Nunomura A, Perry G, Smith MA. The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides. 2002 Jul;23(7):1333-41. PubMed.
Smith MA, Joseph JA, Atwood CS, Perry G. Dangers of the amyloid-beta vaccination. Acta Neuropathol. 2002 Jul;104(1):110. PubMed.
View all comments by Akihiko NunomuraThe experiments described by Head et al. may not elucidate the role played by senile plaques in AD dementia, but they do bolster the idea that amyloid disruption therapy is likely to be most efficacious when administered early in the course of the disease or provided on a preventative basis.
The intimate association of vascular disease and AD suggests that in many patients with early signs of dementia, amyloid disruption therapy may be complicated by impaired perfusion and drainage. Such conditions may explain the outcomes observed following the first human vaccination trial in which senile plaques were disrupted, but the amyloid remnants did not exit the brain. That makes the data of Nikolic et al. exciting, as these experiments suggest another means to actually eliminate and/or effectively alleviate the effects of toxic Aβ molecules.
Successful disruption of amyloid plaques will mitigate and perhaps eliminate the cascade of consequential destruction associated with these deposits. But great uncertainties remain regarding the ultimate risks posed by the chronic disturbance of the immobilized amyloid sequestered within plaques. The relative stress resilience of animal model and human neurons may be quite different, making the extrapolation of laboratory results to clinical outcomes such as improvements in cognitive status a challenging endeavor.
We cannot yet delineate precise pathological role(s) of Aβ in AD dementia, nor can we assign with certainty a normal-state function for this evolutionarily conserved molecule. Inducing or infusing high titers of antibody in the periphery to effect a CNS compartment change is still in an experimental stage. Present immunization trials employing this stratagem must be supported by further analyses beyond antibody titers and plaque removal.
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