By Sabrina Pospich and Stefan Raunser
The leading cause of dementia in adults is Alzheimer’s disease ( AD), which ac- counts for more than 80% of dementia cases worldwide (1). This progressive neurodegenerative disorder is defined by the accumulation of toxic senile
amyloid plaques and neurofibrillary tangles
in the brain, accompanied by synapse and
neuron loss (2). The deposits are composed
of misfolded protein aggregates, which can
also be seeded in a prion-like manner ( 3);
AD is therefore commonly characterized as a
protein-misfolding disease. Treatment is lim-
ited to the deceleration of progression and
symptomatic relief (1). On page 116 of this is-
sue, Gremer et al. ( 4) present a near-atomic
resolution structure of amyloid Ab(1– 42)
fibrils, which are the main components of
amyloid plaques found in AD brains (see the
figure). The structure may help to elucidate
the mechanism of plaque formation and fa-
cilitate finding a cure for the disease.
Ab(1– 42) is derived from the amyloid precursor protein (APP), which is sequentially
cleaved by the enzymes b- and g-secretase
in neurons. The precise physiological function of APP and Ab(1– 42) is not well understood ( 3). In AD brains, Ab(1– 42) is not
degraded properly, resulting in the formation of toxic oligomers and aggregates of
amyloid fibrils (2). Ab(1– 42) fibrils exist in
different polymorphs, which may lead to
different pathogenicity ( 5).
The heterogeneous nature of Ab(1– 42) fi-
brils has so far impeded structural analysis
at high resolution. Gremer et al. overcame
this problem by optimizing the buffer con-
ditions (low pH and organic cosolvent) for
recombinantly produced Ab(1– 42) fibrils.
In this way, they obtained highly homoge-
neous fibrils, which were as toxic to cells
as fibrils grown at physiological pH. They
then determined the structure using trans-
mission electron cryo-electron microscopy
(cryo-EM), a powerful tool for studying he-
lical assemblies and other macromolecular
complexes that do not readily crystallize ( 6).
Based on their 4-Å-resolution structure,
Gremer et al. could build an atomic model
of full-length Ab(1– 42) fibrils. Their model
reveals that the fibrils consist of two intertwined protofilaments; the latter are composed of Ab(1– 42) molecules that stack in a
parallel, in-register cross-b sheet structure
(see the figure). The fibrils are not rotationally symmetric; rather, they adopt helical
symmetry. Thus, each filament is polar and
has distinct ends, with implications for the
binding interface of Ab(1– 42) subunits and
for fibril growth.
Gremer et al.’s structure of Ab(1– 42) fibrils partially resembles a recently published
structure of paired helical tau filaments directly extracted from the brain of a deceased
AD patient ( 7). In both fibrils, two protofilaments are helically arranged and adopt an in-register cross-b structure. Tau filaments are
the main component of neurofibrillary tangles, commonly used as primary AD markers (2). As a microtubule-associated protein,
tau normally binds to and stabilizes microtubules associated with neurons to facilitate
axonal transport. In AD brains, it becomes
hyperphosphorylated, misfolds, and eventually aggregates, forming neurofibrillary tangles (see the figure), leading to a breakdown
of the neuron’s transport system (2).
Cross-b sheet patterned fibrils are not
only found in AD. Many normally soluble
proteins and peptides can convert into the
so-called amyloid state ( 8). Although most
Aß(1– 42) and tau build various 4bril
structures that difer in number,
orientation, and structure of strands.
Formation of amyloid plaques
Cleavage of the amyloid precursor protein (APP)
by ß- and γ-secretase leads to formation of
amyloid plaques in the intracellular space.
Cross-; sheet structure, amyloid state
Both tau and Aß(1– 42) have a similar overall
tertiary protein structure.
Formation of neurofbrillary tangles
Misfolding of tau proteins leads to microtubule
amyloid precursor protein and tau tangle formation.
Department of Structural Biochemistry, Max Planck Institute of
Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund,
Germany. Email: firstname.lastname@example.org
BIOCHEMIS TR Y
The molecular basis
of Alzheimer’s plaques
An amyloid fibril structure provides insights into
senile amyloid plaque architecture
6 OCTOBER 2017 • VOL 358 ISSUE 6359 45
Molecular characteristics of Alzheimer’s disease
Amyloid plaques and neurofibrillary tangles that accumulate in an Alzheimer’s brain consist of amyloid fibrils with different components but similar tertiary protein structures.