Is the amyloid hypothesis of Alzheimer's disease therapeutically relevant?

Abstract

The conventional view of AD (Alzheimer's disease) is that much of the pathology is driven by an increased load of β-amyloid in the brain of AD patients (the 'Amyloid Hypothesis'). Yet, many therapeutic strategies based on lowering β-amyloid have so far failed in clinical trials. This failure of β-amyloid-lowering agents has caused many to question the Amyloid Hypothesis itself. However, AD is likely to be a complex disease driven by multiple factors. In addition, it is increasingly clear that β-amyloid processing involves many enzymes and signalling pathways that play a role in a diverse array of cellular processes. Thus the clinical failure of β-amyloid-lowering agents does not mean that the hypothesis itself is incorrect; it may simply mean that manipulating β-amyloid directly is an unrealistic strategy for therapeutic intervention, given the complex role of β-amyloid in neuronal physiology. Another possible problem may be that toxic β-amyloid levels have already caused irreversible damage to downstream cellular pathways by the time dementia sets in. We argue in the present review that a more direct (and possibly simpler) approach to AD therapeutics is to rescue synaptic dysfunction directly, by focusing on the mechanisms by which elevated levels of β-amyloid disrupt synaptic physiology.

Figure 1. Amyloid β-protein generation by normal proteolytic processing of β-APP

APP is shown at the top, with the β-amyloid region in red. APP can be processed through two mutually exclusive pathways. The α-secretase pathway involves an initial cleavage by α-secretase which goes through the β-amyloid region, precluding further processing that can yield β-amyloid. This initial cleavage event releases sAPP-α into the cytosol, and leaves behind the membrane-bound C83 protein. Processing of C83 by γ -secretase yields the p3 fragment and the AICD. β-Secretase cleavage of APP yields sAPP-β and C99, and subsequent processing of C99 yields β-amyloid and the AICD fragment.

Figure 2. β-Amyloid can inhibit synaptic plasticity through a variety of mechanisms

CREB phosphorylation may be inhibited through inhibition of the PKA pathway, the Uch-L1 proteasomal system, aberrant calpain activity, or inhibition of the cGK pathway. In addition, high β-amyloid levels may reduce histone acetylation, which can impair gene expression necessary for learning and memory. See the text for details.