This fascinating paper by Kurnellas et al. follows up on their previous work showing immunomodulatory properties of amyloid peptides (Aβ40 and 42) and αB-crystallin in ameliorating experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.

This paper provides an in-depth mechanistic analysis of this phenomenon, suggesting that the amyloidogenic proteins and peptides affect the immune response by either mediating chaperone-like activity and/or binding and “scavenging” potential inflammatory mediators including ApoE, complement, etc., from the plasma. In terms of Alzheimer’s disease, while it is well documented that various assemblies of amyloid-β can be toxic to neurons and affect synaptic activity, these data support a potential beneficial role of Aβ peptides in the CNS and in the periphery. To date, it is not known and is still debated what the normal physiological function of the amyloid peptide is. Indeed, Aβ peptides bind ApoE, and this interaction is involved in the clearance/degradation pathways of Aβ peptides from the brain. Thus, based on the data...  Read more

This fascinating paper by Kurnellas et al. follows up on their previous work showing immunomodulatory properties of amyloid peptides (Aβ40 and 42) and αB-crystallin in ameliorating experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.

This paper provides an in-depth mechanistic analysis of this phenomenon, suggesting that the amyloidogenic proteins and peptides affect the immune response by either mediating chaperone-like activity and/or binding and “scavenging” potential inflammatory mediators including ApoE, complement, etc., from the plasma. In terms of Alzheimer’s disease, while it is well documented that various assemblies of amyloid-β can be toxic to neurons and affect synaptic activity, these data support a potential beneficial role of Aβ peptides in the CNS and in the periphery. To date, it is not known and is still debated what the normal physiological function of the amyloid peptide is. Indeed, Aβ peptides bind ApoE, and this interaction is involved in the clearance/degradation pathways of Aβ peptides from the brain. Thus, based on the data in this paper, it is tempting to speculate that this interaction can also then affect the binding and clearance of other proteins, including potential inflammatory mediators in the brain or periphery in response to injury and aging.

We know now that with age, the amyloid peptide clearance pathways are reduced/not efficient. Does this dysfunction in amyloid clearance lead to increased inflammatory reactions in the brain with age? Or will anti-Aβ treatment strategies in AD affect the inflammatory response in the brain? At this point, more data regarding the mechanism of this phenomenon are still warranted. The fact that this treatment strategy results in a rapid reduction in EAE disease progression suggests potential alternative mechanisms of action, or that peripheral injection of amyloidogenic peptides simply affect multiple pathways of the immune system either specifically or non-specifically.

View all comments by Pritam Das

Together with their previous study (1), this paper from the Steinman group leaves little doubt that Aβ peptides (both 40 and 42) exert beneficial effects in the EAE mouse model of MS; they do so by reducing neuroinflammation and attenuating paralysis. The current study also points to the potential underlying mechanisms (chaperon/chelating activity) and identifies hexameric peptides from the C-terminal end of Aβ40 and Aβ42 (among others) as therapeutic agents. The authors suggest that a similar mechanism could be operative in conditions such as stroke and brain trauma where inflammation is seen. This raises a question: What about AD? What implications do these findings have regarding our view of AD pathogenesis and the anti-amyloid therapeutic trials currently underway?

Based on these findings, it might be tempting to think of Aβ as being "good" in AD. Atwood and colleagues had previously suggested Aβ to be beneficial based on its ability to chelate redox metal ions and thereby exert antioxidant effects (2). Incidentally, oxidative stress induces inflammation, whereas...  Read more

Together with their previous study (1), this paper from the Steinman group leaves little doubt that Aβ peptides (both 40 and 42) exert beneficial effects in the EAE mouse model of MS; they do so by reducing neuroinflammation and attenuating paralysis. The current study also points to the potential underlying mechanisms (chaperon/chelating activity) and identifies hexameric peptides from the C-terminal end of Aβ40 and Aβ42 (among others) as therapeutic agents. The authors suggest that a similar mechanism could be operative in conditions such as stroke and brain trauma where inflammation is seen. This raises a question: What about AD? What implications do these findings have regarding our view of AD pathogenesis and the anti-amyloid therapeutic trials currently underway?

Based on these findings, it might be tempting to think of Aβ as being "good" in AD. Atwood and colleagues had previously suggested Aβ to be beneficial based on its ability to chelate redox metal ions and thereby exert antioxidant effects (2). Incidentally, oxidative stress induces inflammation, whereas antioxidants reduce inflammation. The possibility that Aβ can be beneficial is obviously controversial and runs against the very essence of the amyloid hypothesis.

However, I do not think the current investigations can be directly compared to AD or interpreted as supportive of the beneficial role of Aβ in Alzheimer's. The EAE model, by its very nature, is an "acute" system where the disease symptoms (paralysis) appear within days, and animals respond to the treatment on the same time scale. AD, by contrast, is a chronic disorder, and AD-like pathology needs months to manifest in animal models. Etiopathogenesis of MS and AD, and the courses of the respective diseases, are too different to make a direct, valid comparison.

Nonetheless, there are lessons to be learned for the AD field. First, if Aβ is immunosuppressive, then reducing its levels might enhance neuroinflammation and thereby negate any potential beneficial effects of reducing brain amyloid. Is that why the amyloid therapies have been ineffective in improving clinical outcomes? Second, these papers unequivocally demonstrate that levels of Aβ in the peripheral system have significant consequences in the CNS in terms of immune response. Thus, manipulating Aβ levels (by active/passive immunization or by pharmacological drugs) may have significant, unintended consequences, especially in the long term.

References:
1. Grant JL, Ghosn EE, Axtell RC, Herges K, Kuipers HF, Woodling NS, Andreasson K, Herzenberg LA, Herzenberg LA, Steinman L. Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med. 2012 Aug 1;4(145):145ra105. Abstract

2. Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN. Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β. Brain Res Brain Res Rev. 2003 Sep;43(1):1-16. Abstract

View all comments by Sanjay W. Pimplikar