It is time to say that the large, easy-to-detect plaques are outdated. An emerging body of evidence suggests that oligomers are the important toxic entities in Alzheimer disease. The work of Sylvain Lesne and Karen Ashe elegantly demonstrated this in an animal model (Lesne et al., 2006 and Lesne et al., 2008). Moreover, plaques are frequent in normal humans (Aizenstein et al., 2008 and Reiman et al., 2009).

In this paper, Sam Gandy and colleagues report fresh and powerful evidence. The authors used an in vivo model of AD that produces soluble oligomers (oAβ/ADDLs). Specifically, they provide evidence that an APPE693Q single-transgenic mouse developed oAβ/ADDLs without the formation of β amyloid plaques. Interestingly, this mouse model exhibits robust accumulation of intraneuronal APP/Aβ-immunopositivity associated with the multivesicular bodies (MVBs/lipofucsin) of the late endosomal/lysosomal...  Read more

It is time to say that the large, easy-to-detect plaques are outdated. An emerging body of evidence suggests that oligomers are the important toxic entities in Alzheimer disease. The work of Sylvain Lesne and Karen Ashe elegantly demonstrated this in an animal model (Lesne et al., 2006 and Lesne et al., 2008). Moreover, plaques are frequent in normal humans (Aizenstein et al., 2008 and Reiman et al., 2009).

In this paper, Sam Gandy and colleagues report fresh and powerful evidence. The authors used an in vivo model of AD that produces soluble oligomers (oAβ/ADDLs). Specifically, they provide evidence that an APPE693Q single-transgenic mouse developed oAβ/ADDLs without the formation of β amyloid plaques. Interestingly, this mouse model exhibits robust accumulation of intraneuronal APP/Aβ-immunopositivity associated with the multivesicular bodies (MVBs/lipofucsin) of the late endosomal/lysosomal system. The researchers suggest that the intraneuronal accumulation of APP/Aβ observed in this mouse model may represent one site for the initiation of oAβ/ADDLs formation.

This study has the novelty to analyze for the first time the effects of oAβ/ADDLs generated in brain in situ, since all studies to date have involved external application of intracerebral injection of partially purified oAβ/ADDLs preparations.

This study also reports that 12-month-old APPE693Q mice displayed an oAβ/ADDLs-dependent delay in acquisition of the Morris water maze (MWM) task compared to non-transgenic littermates, suggesting that more discrete deficits of spatial orientation may be an early marker of AD-like cognitive decline. These exciting data suggest that 12-month-old APPE693Q mice may represent a “preclinical” model for AD.

Furthermore, this study opens the possibility of using a days-to-criterion analysis as a sensitive measure of pre-pathological oAβ/ADDLs-related clinical deficits in the acquisition of a task requiring spatial orientation.

The only missing piece of data we note in this report is a detailed biochemical analysis of the oligomers in the impaired mice.

View all comments by Rakez Kayed
View all comments by Cristian Lasagna

It is always my pleasure to read such a wonderful paper. However, I always wonder why the clinical trials of amyloid treatment fail.

Amyloid itself shows toxicity in Alzheimer’s model mice, but in the case of humans, amyloid itself does not show any toxicity in Alzheimer’s patients, because amyloid treatment did reduce amyloid level in human brain, but the cognitive impairment did not reverse.

Alzheimer’s model mice do show cognitive recovery when amyloid level is reduced by amyloid treatment, but humans do not show any recovery of cognitive impairment. Why?

These discrepancies force us to consider that there must be a difference in the pathological process between humans and mice. One thing I have found is that urinary homocysteic acid (HA) excretion was very different between humans and mice. Human urinary HA level was very high compared to that of mice (1). This HA was also reported as a possible pathogen of Alzheimer disease (2). Yes, HA toxicity was also observed in mice. But HA level was very low in mice. However, HA toxicity was very strong even when amyloid...  Read more

It is always my pleasure to read such a wonderful paper. However, I always wonder why the clinical trials of amyloid treatment fail.

Amyloid itself shows toxicity in Alzheimer’s model mice, but in the case of humans, amyloid itself does not show any toxicity in Alzheimer’s patients, because amyloid treatment did reduce amyloid level in human brain, but the cognitive impairment did not reverse.

Alzheimer’s model mice do show cognitive recovery when amyloid level is reduced by amyloid treatment, but humans do not show any recovery of cognitive impairment. Why?

These discrepancies force us to consider that there must be a difference in the pathological process between humans and mice. One thing I have found is that urinary homocysteic acid (HA) excretion was very different between humans and mice. Human urinary HA level was very high compared to that of mice (1). This HA was also reported as a possible pathogen of Alzheimer disease (2). Yes, HA toxicity was also observed in mice. But HA level was very low in mice. However, HA toxicity was very strong even when amyloid level was decreased in humans. So we should consider HA toxicity in Alzheimer disease, after amyloid levels are decreased by amyloid treatment.

References:
1. Hasegawa comment on Hardy hypothesis "A critical reappraisal of the Amyloid Hypothesis, in response to inconclusive clinical trial results." Hasegawa T.

2. Hasegawa T, Mikoda N, Kitazawa M, LaFerla FM (2010) Treatment of Alzheimer’s Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice. PLoS ONE 5(1): e8593. Abstract

View all comments by Tohru Hasegawa