Project: Research project

Project Details


Presenile and senile dementia of the Alzheimer's type is presently one of
the most important causes of disability. Histopathologically Alzheimer's
disease is characterized by distinct features foremost of which is the
presence of senile plaques which contain material meeting all the criteria
for amyloid. Indeed, fibrillar deposits which stain with Congo red to give
green birefringence by polarization microscopy are usually found in the
senile plaques in patients with Alzheimer's disease as well as in the walls
of intracerebral blood vessels. Whether there is one or more than one
amyloid substance in these locations is not known. Furthermore, it is not
known whether the amyloid substance is reactive in nature and/or plays a
primary role in the pathogenesis of the dementia. The objective of this proposal is to isolate and characterize the protein
or proteins which are contained in the intracerebral amyloid deposits in
Alzheimer's disease. The working hypothesis is that the amyloid deposits
are composed of a small subunit protein which is deposited in a beta
pleated sheet configuration as has been shown for immunoglobulin light
chains in primary amyloidosis, protein AA in secondary amyloidosis and
prealbumin in hereditary amyloidosis. It is proposed to isolate the
amyloid fibrils from central nervous system tissues of patients dying with
Alzheimer's disease and use these fibril preparations to isolate the
subunit protein or proteins. Light microscopy of Congo red stained
materials and electron microscopy will be used to follow the extraction
procedure as well as to analyze the amount of amyloid material in
individual brains and demonstrate the feasibility of extraction
procedures. Chemical analysis of the amyloid fibril preparations will be
done by solubilizing the amyloid fibrils in denaturing solvents and
fractionation by chromatography both on Sepharose gels and by high
performance liquid chromatography. Amino acid analysis of isolated subunit
proteins and amino acid sequencing of tryptic peptides of the subunit
proteins will be used to characterize the isolated products. The chemical
characterization by primary structure of amyloid subunit proteins in
Alzheimer's disease will allow the determination of whether the amyloid is
a product of 1) normal proteins such as neuroendocrine peptide or
prealbumin, 2) a variant form of a normal human protein such as has been
described for prealbumin variants in hereditary amyloidosis or 3) the
product of an infectious agent such as has been suggested in scrapie.
Effective start/end date4/1/8511/30/86


  • National Institutes of Health


  • Medicine(all)

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