Montine TJ, Larson EB.
Late-life dementias: does this unyielding global challenge require a broader view?.
JAMA. 2009 Dec 16;302(23):2593-4.
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Tarenflurbil, a γ-secretase modulator, failed in Phase 3 trial. Recent clinical failures of amyloid treatment including tarenflurbil have brought confusion to the Alzheimer’s field, which should consider the pathogenic differences of amyloid between Alzheimer’s model mice and humans. Anti-amyloid treatment in model mice succeeded in recovering the cognitive abilities of mice, but not humans.
Why? In their commentary, Montine and Larson explain the possibility that “Commonly used experimental models of Alzheimer disease may inadequately reflect the complexity of cognitive impairment and dementia in older patients and thereby provide falsely promising leads.”
Our research team has found that homocysteic acid (HA), which is metabolized from homocysteine or methionine, is a pathogen for Alzheimer disease. This pathogen basically works under amyloid toxicity. We confirmed this pathogenic action of HA with a newly developed HA vaccine for 3xTg-AD mice (1). First, the mice showed higher HA levels prior to amyloid-induced pathological changes. Second, the HA vaccine recovered the cognitive disability of the mice independently from amyloid toxicity.
Humans excrete HA into urine at 1,000 times higher concentration than mice, which implies that humans have more severe HA toxicity than do mice (2). When anti-amyloid treatment decreases the amyloid level in mouse brain, then HA toxicity appears in mice, but HA levels in mice are low and its toxicity is weak. In contrast, HA levels are much higher in humans, and HA itself shows strong toxicity. In conclusion, we should consider the pathogenic effect of HA in human Alzheimer disease.
Hasegawa, T. Differences in urinary excretion of homocysteic acid (HA) have been observed between humans and mice, suggesting that HA toxicity is more severe in humans than mice.
In a paper in the Journal of Alzheimer's Disease, we demonstrate that the oxysterol 27-hydroxycholesterol reduces leptin levels and increases levels of both Aβ and phosphorylated tau in organotypic slices from adult rabbit hippocampus. Interestingly, we show that treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β, respectively. Our results suggest that cholesterol metabolites induce AD-like pathology by altering leptin signaling.
What has always been remarkable about preclinical work in mice is just how extraordinarily plastic amyloid deposits are in the mouse brain. I can recall numerous discussions with colleagues leading to the inevitable point that an inordinately high proportion of potential therapeutics significantly reduce Aβ in transgenic mice. This is a problem that echoes one in the cancer field (it has often been said that cancer was cured in mice a decade ago, but success at translating these findings into human patients has been poor). Not only does this situation cast doubt on our models of the disease itself, but makes one wonder if mice in general are a poor system in which to study Alzheimer disease.
It's amazing to have to read the "blame it on the mouse models" excuse.
Those working with mice know well: mice are not patients and definitely not AD patients. They "model" one or the other aspect of AD, in most cases (over)production of Aβ peptides and other APP metabolites, a fact often set aside in the pharma sector for temporary ease of mind.
So is the fact that putting in not one but three or five mutations accelerates the process, but does not necessarily improve the preclinical relevance of the model. Adding the odd mutant PS1 is defensible for mechanistic revelations of its actions on "85+ substrates," but as an amyloid , this is hardly relevant for the aged Phase 3 trial participant.
Models are what they are: living "test tubes" of higher-order complexity than a solution of recombinant enzyme, but never the "real thing." The only efficacy test tube of any compound or treatment is the clinic. It's too bad if they fail there…telling the model-makers that square one is still open for trying harder!