. 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. PubMed.

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  1. These results are highly unexpected and in need of replication, but they are also very interesting in the light of what we currently know about Aβ homeostasis in several diseases of severe neuroinflammation, for example, bacterial meningitis, HIV-associated dementia, and multiple sclerosis. In these conditions, CSF levels of Aβ38, 40, and 42; soluble APP fragments; and BACE1 are lower than in neurologically healthy controls and or in AD patients. Perhaps a general reduction in the expression of APP-derived proteins plays a role in neuroinflammation?

    View all comments by Henrik Zetterberg
  2. Steinman suggests that their results could imply a protective or pathological role for Aβ, depending on the context (i.e., good in MS, bad in AD).

    However, together with evidence showing an apparent protective role for Aβ in the brain against a variety of stress stimuli, including microglia activation, ROS, and cholesterol dysregulation (Castellani et al., 2009; Castello and Soriano, 2012), their results would be consistent with an alternative scenario, in which Aβ has a bona fide protective function, both in blood and in brain.

    That protective role would be achieved within a tightly regulated concentration range of Aβ, and dysregulation leading to peptide concentrations outside of that optimal range would lead, or contribute, to pathology. That would be true whether there is too little or too much Aβ.

    The obvious implication is that the current efforts to reduce Aβ levels in healthy brains as an approach to preventing AD are likely to be neutral at best, and would accelerate neuronal dysfunction at worst.

    It would seem that we need a better understanding of the basic biology of Aβ (and of its precursor APP) if we want to successfully determine whether amyloid-centric approaches to AD are scientifically sound or ought to be discontinued.

    View all comments by Salvador Soriano