- Protein biochemistry of the brain amyloid ß peptides
Alzheimer's disease (AD) is a neurodegenerative dementia affecting the
brain and characterized by severe amyloidosis. The molecular cause of AD is
unknown. Amyloid plaques that are an invariant neuropathologic feature of AD
affected brains are composed of ~4.5 kDa Aß peptide and its derivatives. The
physiological function of neither APP nor Aß is known. Since Aß contains a
hydrophobic C-terminus implicated in the initiation of deposits, it was of
interest to establish which of the two variants, AßX-40 or AßX-42, contributes
to plaque development. The longer Aß1-42 has been detected as the dominant
form in plaques.
We have established that in brains of Down's syndrome individuals specific
Aß peptides precede amyloid formation. The longer Aß42 initiates deposition
but the N-terminal truncation of the peptide constitutes a critical factor in
AD pathology. The major diffusable Aß peptides, besides the full-length form,
start at positions 3 and 11 and have their N-terminal glutamates cyclized. Our
study of AD brains from carriers of APP and presenilin mutations, shows that
despite genetic and phenotypic heterogeneity a common pattern of Aß processing
in the brain underscores the role of the N-terminally truncated and modified
peptides in the disease.
- Molecular interactions of brain amyloid precursor protein (APP)
Excessive accumulation of Aß seems to be the major causative factor in
AD. Since Aß is a proteolytic product of APP most of research efforts
are directed towards understanding the role of APP. Molecular studies
utilizing the yeast two-hybrid technology revealed that proteins such as Fe65
and X11 are prime candidates to play an organizing role in the plasma membrane
localization and function of APP. We use the two-hybrid technique to search
for proteins specifically interacting within the APP complex. Recently, we
turned our attention to the PDZ domain of X11 and isolated the
X11-PDZ-interacting protein - XBP, that is another member of a growing family
of proteins constituting a multi-protein APP complex. Its function, like other
adaptor proteins, might involve positioning and regulation of APP within the
complex. Revealing all the components of this network will help in
understanding the APP function, its direct involvement in AD pathology and
will hopefully suggest new therapeutic strategies to control Aß production in
the brain.
- Teller JK, Russo C, DeBusk L, Angelini G, Zaccheo D,
Dagna-Bricarelli F, Scartezzini P, Mann DMA, Tabaton M, Gambetti P
(1996)
Presence of soluble amyloid ß peptide
precedes amyloid plaque formation in Down's syndrome.
Nature Med 2, 93-95.
- Russo C, Saido TC, DeBusk LM, Tabaton M, Gambetti P,
Teller JK (1997)
Heterogeneity of water-soluble
amyloid ß-peptide in Alzheimer's disease and Down's syndrome
brains.
FEBS Lett 409, 411-416.
- Teller JK (1998)
Amyloid ß
and the pathogenesis of Alzheimer's disease.
Current Research in Alzheimer's Disease 3,
145-150.
- Russo C, Angelini G, Dapino D, Piccini A, Piombo G,
Schettini G, Chen S, Teller JK, Zaccheo D, Gambetti P, Tabaton M.
(1998)
Opposite roles of apolipoprotein E in
normal brains and in Alzheimer's disease.
Proc
Natl Acad Sci U S A. 95, 15598-602.
- Russo C, Schettini G, Saido TC, Hulette C, Lippa C,
Lannfelt L, Ghetti B, Gambetti P, Tabaton M, Teller JK (2000)
Presenilin-1 mutations in Alzheimer's disease.
Nature 405, 531-532.
- Gambetti P, Parchi P, Capellari S, Russo C, Tabaton M,
Teller JK, Chen SG (2001)
Mechanisms of
phenotypic heterogeneity in prion, Alzheimer and other conformational
diseases.
J.Alzheimer's Disease 3,
87-95.
- Russo C, Salis S, Dolcini V, Venezia V, Song X, Teller
JK,Schettini G (2001)
Amino-terminal
modification and tyrosine phosphorylation of carboxy-terminal fragments of
the amyloid precursor protein in Alzheimer's disease and Down's syndrome
brain.
Neurobiology of Disease 8,
173-180.
Dr. Jan K. Teller
East Carolina University
Brody School of Medicine
Physiology Department
600 Moye Blvd.
6W-39 Brody Bldg.
Greenville, NC 27858-4354
