Psychiatric News January 4, 2002
Volume 37 Number 1
© 2002 American Psychiatric Association
p. 20
Soluble Beta Amyloid Grows As Alzheimer’s Culprit
Jim Rosack
A new study using an animal model of Alzheimer’s disease adds to the evidence that soluble forms of beta amyloid may be more important in causing memory impairment than insoluble amyloid plaques deposited in the brain.
A new study reported in the December 4, 2001, issue of Proceedings of the National Academy of Sciences is adding to the controversy surrounding the exact cause of Alzheimer’s disease.
The new report suggests that the progressive degeneration of memory that is the hallmark of the disease may develop even in the absence of the disease’s characteristic amyloid plaques.
Researchers at the Institute of Physiology of the Academy of Sciences of the Czech Republic studied two types of mice, both engineered—in different ways—to overproduce beta amyloid precursor protein (ß-APP). ß-APP, when cleaved by the brain enzyme gamma secretase, results in amyloid ß peptides of various sizes. Many researchers have zeroed in on the 42-amino-acid-long amyloid chain (Aß42) as the likely culprit in the development of the brain plaques commonly found on autopsy of patients with Alzheimer’s disease (Psychiatric News, December 21). However the question of whether the insoluble fibrillar form found in plaques, soluble forms of amyloid, or other intracellular peptides are more harmful in the development of Alzheimer’s disease remains quite controversial.
Two Mouse Strains
The Czech team engineered two different strains of mice, both of which do not form Aß42 plaques, but do have diffuse amyloid ß deposits that follow the anatomic selectivity seen in Alzheimer’s. The patterns of the deposits also resemble the early Alzheimer’s-like deposition of amyloid ß that is seen in young-adult patients with Down syndrome.
The researchers then tested the mice in the Morris Water Maze, a standard device for testing spatial learning abilities. They found age-dependent learning and memory deficits in both strains of the genetically altered mice.
In addition, the researchers tested the mice for their ability to perform several other tasks, including active and passive place-avoidance tasks and open-field tests, to assess "normal" behaviors under known conditions.
In these tests both strains of genetically altered animals performed normally. This, according to the researchers, indicated that the overexpression of ß-APP did not lead to overt dementia.
"Our study demonstrates that overexpression of ß-APP, at levels that are commonly observed in Down’s patients and presumably early Alzheimer’s disease, results in specific spatial learning and memory deficits that are age related," the researchers conclude. "Most importantly, our transgenic animal model does not develop amyloid plaques, suggesting that increased levels of soluble Aß40/42 or [related fragments] are involved in the development of cognitive deficits."
Other Findings
The current study is not the first to stir controversy over the connection between plaques and Alzheimer’s. Soluble forms of ß amyloid have been a hot topic in research circles for some time (Psychiatric News, June 1, 2001).
"In the past few years, many investigators have come to believe that soluble Aß, or what I like to call ‘invisible amyloid,’ is more important than the amyloid deposits or plaques," said Edward Koo, M.D., an associate professor of neurosciences at the University of California at San Diego and a noted amyloid researcher. "Indeed, this harkens back to the old days when plaques and tangles were called ‘tombstone artifacts’ to implicate them as not being central to the disease process."
Koo noted that, logically speaking, "there has to be a stage of pre-aggregated/prefibrillar deposits of amyloid that exist in the brain. This is increasingly being studied and would appear to be more important for disease pathogenesis."
The report "Specific Spatial Learning Deficits Become Severe With Age in ß-amyloid Precursor Protein Transgenic Mice That Harbor Diffuse ß-amyloid Deposits but Do Not Form Plaques," can be accessed on the Web at www.pnas.org by searching on "Koistinaho." 
Proc. Natl. Acad. Sci. USA 2001 98 14675[Abstract/Free Full Text]
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