Soluble Beta Amyloid Grows As Alzheimer’s Culprit
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 (β-APP). β-APP, when cleaved by the brain enzyme gamma secretase, results in amyloid β peptides of various sizes. Many researchers have zeroed in on the 42-amino-acid-long amyloid chain (Aβ42) 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 Aβ42 plaques, but do have diffuse amyloid β 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 β 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 β-APP did not lead to overt dementia.
“Our study demonstrates that overexpression of β-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 Aβ40/42 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 β 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 Aβ, 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 β-amyloid Precursor Protein Transgenic Mice That Harbor Diffuse β-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
Information & Authors
Information
Published In
History
Published online: 4 January 2002
Published in print: January 4, 2002
Notes
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.
Authors
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
There are no citations for this item
View Options
View options
PDF/ePub
View PDF/ePubGet Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).