Considering Intracellular Amyloid Beta in Alzheimer's Disease

There is a growing diversity of views in the Alzheimer's research community regarding mechanisms and future directions, which is probably to be expected given the slow path to results on the consensus approach of removing amyloid β. Here is a representative opinion piece:

Two decades have passed since the discovery of the first proteases that degrade the amyloid β-protein (Aβ), the primary constituent of the amyloid plaques that characterize Alzheimer disease (AD). While significant progress has been made, this is an appropriate juncture to reflect on what has been accomplished and ask which research directions are most likely to bear fruit going forward. Herein, I argue that a renewed focus on intracellular Aβ-degrading proteases (AβDPs) is a highly promising direction for future studies, one that is not only likely to advance our understanding of the fundamental molecular pathogenesis of AD, but also to critically inform the development of effective therapies for use clinically.

To date, most studies of AβDPs have focused predominantly on proteases that act extracellularly. This is not surprising - Aβ is, after all, a secreted peptide, and amyloid plaques form extracellularly. However, there is a growing body of evidence implicating intracellular pools of Aβ in the pathogenesis of AD. Generally speaking, it has been challenging to study specific pools of Aβ in conventional animal models of AD, since most models rely upon overexpression of the β-amyloid precursor protein (APP), which necessarily increases the levels of all pools of Aβ simultaneously. The study of AβDPs, by contrast, offers a unique window into the pathogenic role of Aβ, in no small part because individual AβDPs have unique subcellular localizations and pH profiles, which can be exploited to selectively target different pools of Aβ (e.g., extracellular, lysosomal, etc.). This can be readily achieved by overexpression, genetic deletion or pharmacological manipulation of appropriate AβDPs, either alone or in tandem with APP overexpression.

In conclusion, there is a compelling theoretical and empirical rationale for the field to undertake a renewed focus on intracellular AβDPs. The knowledge we can expect to derive from the study of extracellular AβDPs appears to be, at best, approaching an asymptote and, at worst, revealing that extracellular pools of Aβ may not be involved in the pathogenesis of AD to the extent so widely assumed for so long. The study of intracellular AβDPs, by contrast, seems poised to yield insights into questions that are not merely academic or theoretic, but highly practical - for example, the relative merits of immunotherapies, which only target extracellular Aβ, versus secretase inhibitors or modulators, which affect intracellular Aβ as well. Considering the growing interpersonal, financial and societal impact of AD, and the current lack of therapies, it is wise to pursue any and all avenues that may lead to effective treatments, and the study of intracellular AβDPs seems an especially promising direction for future investigation.



I can't believe that no one is studying intracellular Aβ already. Then again, it might have been that most people thought extracellular Aβ was responsible for Alzheimers, and only the recent failure of antibodies against extracellular Aβ has convinced people otherwise.

Posted by: Jim at September 12th, 2014 4:05 PM
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