A
B
Figure 1 (A) Cross sections of the brain show atrophy, or shrinking, of brain tissue caused by Alzheimer's disease (source: nia.nih.gov). (B)
Aβ plaque pathology in the AD brain (a) spreads in a stereotypical pattern over time (b). Adapted from [8]
A β species from the APP protein or
faulty protein clearance [2]. Follow-
ing this slow accumulation of A β β,
stable “seeds” can form which then
allow exponential aggregation of A β
and the spreading of amyloid pathol-
ogy through the brain similar to prion
diseases, the classic protein-only dis-
ease [7, 8, 9]. This prion-like seeding
phenomenon has been most convinc-
ingly demonstrated in mice express-
ing human APP that have accelerated
deposition of A β throughout the brain
after aggregated A β was injected into
the hippocampus [9, 10, 11, 12, 13].
Astonishingly, different human APP
transgenic mice (APP23 and APPPS1)
also produce unique A β conforma-
tions that can then induce different
A β pathologies [10, 14]. This empha-
sizes that A β is more than a simple
by-product of disease but can induce
prion-like spreading of amyloid de-
posits with remarkably distinct char-
acteristics.
Based on these previous studies, our
group recently undertook a more ex-
tensive characterization of A β matu-
ration within the two above mentioned
mouse models, APP23 and APPPS1.
Our goal was to determine how A β
might change over the lifetime of the
mice. Based on the average life span
of the two mouse lines, 6 age groups
were chosen and the brains of mice
were compared in a variety of ways.
Histology and biochemistry confirmed
that A β levels increased over the life-
time of both lines. However, we were
intrigued to find that the ratio of dif-
ferent A β species was not constant
over time. Namely, the amount of
A β 42 (amino acid length) compared
to A β 40 (amino acid length) was in-
creased in both mouse lines at the
age of onset for A β deposition. We
knew from studies in humans that A β
42/40 is increased in patients with AD
[15, 16]. In order to place this remark-
able finding within a biological con-
text, we injected brain extracts from
these samples into the hippocampus
of APP23 mice. All extracts gener-
ated from ages where A β deposition
was detectable by histology, unsur-
prisingly induced deposition with the
characteristic prion-like spreading we
observed previously (Fig 2). By serially
diluting the brain extracts we were
able to calculate the seeding dose 50
or SD50 (simply the dilution at which
50% of injected animals had induced
A β deposition; similar to lethal dose
50). For both the APP23 and APPPS1
brain extracts, the SD50 plateaued
with increasing age (Fig 3). Strikingly,
when we considered the amount of
A β β in the extracts and calculated the
specific activity (SD50/A β ), there was
a peak for both APP23 and APPPS1
extracts at the age when deposition
was first detected (Fig 3). This sug-
gests that the A β present in mice at
this critical time point of deposition
and, very likely the appearance of the
first seeds, is unique in both biochem-
ical and biological properties.
We feel that this scientific finding,
while interesting from a basic science
perspective, also could have direct im-
plications for AD in a clinical setting.
While the hunt for a therapy targeting
A β β has been extensive, these efforts
have largely failed to have a signifi-
cant effect in human trials. Of note, it
is widely accepted that changes in A β
homeostasis occur decades prior to
the onset of symptoms in AD [3,17].
These disappointing clinical results
could be explained by a failure to ad-
minister treatment early enough to
Figure 2. Aβ deposition is induced in the hippocampus by both APP23 (after 12 months) and APPPS1 (after 3 months) extracts.
Scale bar=200μm. Adapted from Ye et al.
14 | NEUROMAG | November 2017