Soluble pool of A? amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease

TLDR

Alzheimer’s disease is driven by amyloid‑beta production, yet the kinetics, compartmentation, and temporal relationship of soluble versus insoluble Aβ to neurodegeneration remain unclear, with soluble forms present both intracellularly and extracellularly. The study proposes that lowering soluble Aβ to normal control levels could be a therapeutic target. The authors quantified soluble and insoluble Aβ via western blot and related the measurements to disease‑severity markers. Soluble Aβ is tripled in AD and strongly correlates with severity, whereas insoluble Aβ only distinguishes AD from controls and shows no correlation with severity, indicating distinct soluble and insoluble amyloid pools.

Abstract

Genetic evidence strongly supports the view that Aβ amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Aβ and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Aβ were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Aβ is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Aβ (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Aβ, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Aβ that cause neurodegeneration. Reducing the levels of these soluble Aβ species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.