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

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.

Zinc and copper modulate Alzheimer Aβ levels in human cerebrospinal fluid

“…Also, the number of AD cases was relatively small. We did not observe an association of CSF metal levels to neuritic (amyloid) plaques, but it has been previously suggested the amyloid plaques do not correlate with total Aβ42 burden in brain tissue [28]. Also, there were no brain Aβ42 values to compare with the CSF values.…”

Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

“…Increases in the secretion and aggregation of Aβ molecules are thought to be responsible for cell toxicity and memory impairment in AD (Koh et al, 1990;Yankner et al, 1990;Mattson et al, 1992Mattson et al, , 1993Morgan et al, 2000;Naslund et al, 2000). A series of studies have shown that levels of soluble Aβ correlate with the degree of cognitive impairment and disease progression in animal models and AD subjects (Kuo et al, 1996;McLean et al, 1999;Mucke et al, 2000;Naslund et al, 2000) whereas increasing evidence has suggested that soluble non-fibrillar Aβ rather than the insoluble fibrillar counterpart is important for the pathophysiology of the disease (Walsh 1999;Lambert et al, 2000). In addition, LH has been found to cause elevated levels of Aβ in neuroblastoma cells in vitro (Bowen et al, 2004), and the prolonged suppression of LH in both normal mice (Bowen et al, 2004) and an AD mouse model (Casadesus et al, 2006) has been shown to decrease Aβ load and aggregates, respectively, in vivo.…”

Oligomers of the amyloid-β protein disrupt working memory: Confirmation with two behavioral procedures

“…While a number of studies have correlated levels of oligomeric Aβ in brain with poor memory or cognitive performance [e.g., 14,15,16], very few experiments have assessed the cognitive effects of Aβ oligomers. In 2005, it was demonstrated that 7PA2 CM, containing Aβ dimers and trimers but not monomers, disrupted the memory of complex learned behavior when injected into the lateral ventricle of behaving rats [3].…”