Could blocking the formation of amyloid channels rescue Alzheimer's phenotype?

Abstract

In a most simplified way, we can say that much of the symptomatology that characterizes Alzheimer's disease (AD) can be attributed to a cascade of toxic events initiated by the presence in the interstitial space of the brain of oligomers of the β‐amyloid peptide (Aβ) peptide, a cleavage by‐product of the Amyloid precursor protein (APP). Intuitively, it follows that the amyloid peptide is the ideal target to combat this disease. However, several anti‐Aβ therapies failed in clinical trials devoted to find a treatment for AD. However, last year, the results of a clinical trial prompted back the interests in this type of therapy. In this issue of EMBO Molecular Medicine, Martinez Hernandez and colleagues present encouraging results showing that the diphenylpyrazole compound Anle138b prevents and reduces the toxic effects of Aβ in a mouse model of AD (APPPS1ΔE9). Regarding the mechanisms of action, they present good evidence that Anle138b prevents the formation of conducting Aβ pores on artificial membranes and primary hippocampal neurons. While the data are encouraging, AD mouse models only represent part of the AD pathology and clinical trials are needed to determine the usefulness of Anle138b to treat AD patients.

Patients with Alzheimer’s disease have increased cellular amyloid uptake

“…These channels are non-selective and can be extremely large [3, 4, 20, 24, 34]. Channel formation is frequently cited as a molecular mechanism underlying AD [2, 6, 14, 15, 18, 19], but it is usually implied that the channels are formed in the plasma membrane, which does not explain many phenomena associated with the disease [45]. Our hypothesis suggests that amyloid membrane channels are formed in lysosomal membranes rather than in plasma membranes.…”