3 research outputs found
Structural Dynamics of the Amyloid β-Protein Monomer Folding Nucleus
Alzheimer’s disease (AD) is linked to the aberrant
assembly
of the amyloid β-protein (Aβ). The <sup>21</sup>AEDVGSNKGA<sup>30</sup> segment, Aβ(21–30), forms a turn that acts
as a monomer folding nucleus. Amino acid substitutions within this
nucleus cause familial forms of AD. To determine the biophysical characteristics
of the folding nucleus, we studied the biologically relevant acetyl-Aβ(21–30)-amide
peptide using experimental techniques (limited proteolysis, thermal
denaturation, urea denaturation followed by pulse proteolysis, and
electron microscopy) and computational methods (molecular dynamics).
Our results reveal a highly stable foldon and suggest new strategies
for therapeutic drug development
Amyloid β‑Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer’s Disease Mutation
Oligomeric
states of the amyloid β-protein (Aβ) appear to be causally
related to Alzheimer’s disease (AD). Recently, two familial
mutations in the amyloid precursor protein gene have been described,
both resulting in amino acid substitutions at Ala2 (A2) within Aβ.
An A2V mutation causes autosomal recessive early onset AD. Interestingly,
heterozygotes enjoy some protection against development of the disease.
An A2T substitution protects against AD and age-related cognitive
decline in non-AD patients. Here, we use ion mobility-mass spectrometry
(IM-MS) to examine the effects of these mutations on Aβ assembly.
These studies reveal different assembly pathways for early oligomer
formation for each peptide. A2T Aβ42 formed dimers, tetramers,
and hexamers, but dodecamer formation was inhibited. In contrast,
no significant effects on Aβ40 assembly were observed. A2V Aβ42
also formed dimers, tetramers, and hexamers, but it did not form dodecamers.
However, A2V Aβ42 formed trimers, unlike A2T or wild-type (wt)
Aβ42. In addition, the A2V substitution caused Aβ40 to
oligomerize similar to that of wt Aβ42, as evidenced by the
formation of dimers, tetramers, hexamers, and dodecamers. In contrast,
wt Aβ40 formed only dimers and tetramers. These results provide
a basis for understanding how these two mutations lead to, or protect
against, AD. They also suggest that the Aβ N-terminus, in addition
to the oft discussed central hydrophobic cluster and C-terminus, can
play a key role in controlling disease susceptibility
Role of Species-Specific Primary Structure Differences in Aβ42 Assembly and Neurotoxicity
A variety of species express the
amyloid β-protein (Aβ
(the term “Aβ” refers both to Aβ40 and Aβ42,
whereas “Aβ40” and “Aβ42”
refer to each isoform specifically). Those species expressing Aβ
with primary structure identical to that expressed in humans have
been found to develop amyloid deposits and Alzheimer’s disease-like
neuropathology. In contrast, the Aβ sequence in mice and rats
contains three amino acid substitutions, Arg5Gly, His13Arg, and Tyr10Phe,
which apparently prevent the development of AD-like neuropathology.
Interestingly, the brush-tailed rat, Octodon degus, expresses Aβ containing only one of these substitutions,
His13Arg, and <i>does</i> develop AD-like pathology. We
investigate here the biophysical and biological properties of Aβ
peptides from humans, mice (Mus musculus), and rats (Octodon degus). We find
that each peptide displays statistical coil → β-sheet
secondary structure transitions, transitory formation of hydrophobic
surfaces, oligomerization, formation of annuli, protofibrils, and
fibrils, and an inverse correlation between rate of aggregation and
aggregate size (faster aggregation produced smaller aggregates). The
rank order of assembly rate was mouse > rat > Aβ42. The
rank
order of neurotoxicity of assemblies formed by each peptide immediately
after preparation was Aβ42 > mouse ≈ rat. These data
do <i>not</i> support long-standing hypotheses that the
primary factor controlling development of AD-like neuropathology in
rodents is Aβ sequence. Instead, the data support a hypothesis
that assembly quaternary structure <i>and</i> organismal
responses to toxic peptide assemblies mediate neuropathogenetic effects.
The implication of this hypothesis is that a valid understanding of
disease causation within a given system (organism, tissue, etc.) requires
the coevaluation of both biophysical and cell biological properties
of that system