PRION2015 Alzheimer’s disease
*** P.34: Preliminary study of Alzheimer’s disease transmission to bank
vole
Guido Di Donato1, Geraldina Riccardi1, Claudia D’Agostino1, Flavio
Torriani1, Maurizio Pocchiari2, Romolo Nonno1, Umberto Agrimi1, and Michele
Angelo Di Bari1
1Department of Food Safety and Veterinary Public Health Istituto Superiore
di Sanit a, Rome, Italy; 2Department of Cellular Biology and Neuroscience;
Istituto Superiore di Sanit a, Rome, Italy
Extensive experimental findings indicate that prion-like mechanisms underly
the pathogenesis of Alzheimer disease (AD). Transgenic mice have been pivotal
for investigating prionlike mechanisms in AD, still these models have not been
able so far to recapitulate the complex clinical-pathological features of AD.
Here we aimed at investigating the potential of bank vole, a wild-type rodent
highly susceptible to prions, in reproducing AD pathology upon experimental
inoculation.
Voles were intracerebrally inoculated with brain homogenate from a familial
AD patient. Animals were examined for the appearance of neurological signs until
the end of experiment (800 d post-inoculation, d.p.i.). Brains were studied by
immunohistochemistry for pTau Prion 2015 Poster Abstracts S29 (with AT180 and
PHF-1 antibodies) and b-amyloid (4G8).
Voles didn’t show an overt clinical signs, still most of them (11/16) were
found pTau positive when culled for intercurrent disease or at the end of
experiment. Interestingly, voles culled as early as 125 d.p.i. already showed
pTau aggregates. Deposition of pTau was similar in all voles and was
characterized by neuropil threads and coiled bodies in the alveus, and by rare
neurofibrillary tangles in gray matter. Conversely, b-amyloid deposition was
rather rare (2/16). Nonetheless, a single vole showed the contemporaneous
presence of pTau in the alveus and a few Ab plaque-like deposits in the
subiculum. Uninfected age-matched voles were negative for pTau and Ab.
*** These findings corroborate and extend previous evidences on the
transmissibility of pTau and Ab aggregation. Furthermore, the observation of a
vole with contemporaneous propagation of pTau and Ab is intriguing and deserves
further studies.
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P.155: Quantitative real-time analysis of disease specific tau amyloid
seeding activity
Davin Henderson and Edward Hoover Prion Research Center; College of
Veterinary Medicine and Biomedical Sciences; Colorado State University; Fort
Collins, CO USA
A leading hypothesis for the cause of neurodegenerative diseases is the
templated misfolding of cellular proteins to an amyloid state. Spongiform
encephalopathies were the first diseases discovered to be caused by a misfolded
amyloid-rich protein. It is now recognized that the major human
neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s
disease (PD), and chronic traumatic encephalopathy (CTE), also are associated
with amyloid formation. Moreover, AD and PD amyloids have been shown competent
to transmit disease in experimental animal models, suggesting shared mechanisms
with traditional prion diseases. Sensitive detection of prion disease has been
advanced by in vitro amplification of low levels of disease specific amyloid
seeds, e.g. serial protein misfolding amplification (sPMCA), amyloid seeding
(ASA) and real-time quaking induced conversion (RT-QuIC), thereby replicating
the disease process in vitro. In addition, measurement of the amyloid formation
rate can estimate the level of disease-associated seed by using methods
analogous to quantitative polymerase chain reaction (qPCR). In the present work,
we apply these principles to show that seeding activity of in vitro generated
amyloid tau and AD brain amyloid tau can be readily detected and
quantitated.
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P.83: Gerstmann-Str€aussler-Scheinker disease with F198S mutation:
Selective propagation of PrPSc and pTau upon inoculation in bank vole
Michele Angelo Di Bari1, Romolo Nonno1, Laura Pirisinu1, Claudia
D’Agostino1, Geraldina Riccardi1, Guido Di Donato1, Paolo Frassanito1,
Bernardino Ghetti2, Pierluigi Gambetti3, and Umberto Agrimi1
1Department of Veterinary Public Health and Food Safety; Istituto Superiore
di Sanit a; Rome, Italy;
2Indiana University-Purdue University Indianapolis; Department of Pathology
and Laboratory Medicine; Indianapolis, IN USA; 3Case Western Reserve University;
Cleveland, OH USA
Gerstmann-Str€aussler-Scheinker disease with F198S mutation (GSS-F198S) is
characterized by the presence of PrP amyloid plaques as well as neurofibrillary
tangles with abnormally-phosphorylated tau protein (pTau) in the brain. The
relationship between tau protein and PrP in the pathogenesis of GSS-F198S is
unknown. In a previous study, we inoculated intracerebrally 2 GSS-F198S cases in
2 lines of voles carrying either methionine (Bv109M) or isoleucine (Bv109I) at
codon 109 of PrP. GSS-F198S transmitted rather efficiently to Bv109I, but not to
Bv109M.
Here we investigated the presence of pTau, as assessed by
immunohistochemistry with anti-pTau antibodies AT180 and PHF-1, in the same
voles previously inoculated with GSSF198S. Among these voles, most Bv109I showed
clinical signs after short survival times (»150 d.p.i.) and were positive for
PrPSc. The remaining Bv109I and all Bv109M survived for longer times without
showing prion-related pathology or detectable PrPSc. All Bv109I which were
previously found PrPSc-positive,
S54 Prion 2015 Poster Abstracts
were immunonegative for pTau deposition. In contrast, pTau deposition was
detected in 16/20 voles culled without clinical signs after long survival times
(225–804 d.p.i.). pTau deposition was characterized by neuropil threads and
coiled bodies in the alveus, and was similar in all voles analyzed.
These findings highlight that pTau from GSS-F198S can propagate in voles.
Importantly, pTau propagation was independent from PrPSc, as pTau was only found
in PrPSc-negative voles surviving longer than 225 d.p.i. Thus, selective
transmission of PrPSc and pTau proteinopathies from GSS-F198S can be
accomplished by experimental transmission in voles.
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I3 Aβ Strains and Alzheimer’s Disease
Lary Walker Emory University, Atlanta, GA, USA
An essential early event in the development of Alzheimer’s disease is the
misfolding and aggregation of Aβ. Enigmatically, despite the extensive
deposition of human-sequence Aβ in the aging brain, nonhuman primates do not
develop the full pathologic or cognitive phenotype of Alzheimer’s disease, which
appears to be unique to humans. In addition, some humans with marked Aβ
accumulation in the brain retain their cognitive abilities, raising the question
of whether the pathogenicity of Aβ is linked to the molecular features of the
misfolded protein. I will present evidence for strain-like molecular differences
in aggregated Aβ between humans and nonhuman primates, and among end-stage
Alzheimer patients. I will also discuss a case of Alzheimer’s disease with
atypical Aβ deposition to illustrate heterogeneity in the molecular architecture
of Aβ assemblies, and how this variability might influence the nature of the
disease. As in the case of prion diseases, strain-like variations in the
molecular architecture of Aβ could help to explain the phenotypic variability in
Alzheimer’s disease, as well as the distinctively human susceptibility to the
disorder.
This research was conducted in collaboration with Harry LeVine, Rebecca
Rosen, Amarallys Cintron, David Lynn, Yury Chernoff, Anil Mehta and Mathias
Jucker and colleagues. Supported by AG040589, RR165/OD11132, AG005119, NS077049,
the CART Foundation and MetLife.
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I5 Pathogenic properties of synthetically generated prions
Jiyan Ma Van Andel Research Institute, Grand Rapids, Michigan, USA
Synthetically generating prions with bacterially expressed recombinant
prion protein (recPrP) strongly supports the prion hypothesis. Yet, it remains
unclear whether the pathogenic properties of synthetically generated prions
(rec-Prion) fully recapitulate those of naturally occurring prions. A series of
analyses including intracerebral and intraperitoneal transmissions of rec-Prion
in wild-type mice were performed to determine the characteristics of rec-Prion
induced diseases. Results from these analyses demonstrated that the rec-Prion
exhibits the same pathogenic properties with naturally occurring prions,
including a titratable infectivity that can be determined by endpoint titration
assays, capability of transmitting prion disease via routes other than the
direct intra-cerebral inoculation, causing ultra-structural lesions that are
specific to prion disease, and sharing a similar manner of visceral
dissemination and neuroinvasion with naturally occurring scrapie and chronic
wasting disease. These findings confirmed that the disease caused by rec-Prion
in wild-type mice is bona fide prion disease or transmissible spongiform
encephalopathiges, and the rec-Prion contains similar pathogenic properties as
naturally occurring prions.
I6 Transmissible protein toxins in neurodegenerative disease
Jacob Ayers, David Borchelt University of Florida, Gainesville, FL,
USA
Amyotrophic lateral sclerosis (ALS) is an obvious example of
neurodegenerative disease that seems to spread along anatomical pathways. The
spread of symptoms from the site of onset (e.g. limb) to the respiratory
musculature drives the rate of disease progression. In cognitive disorders, such
as Alzheimer’s disease, one can find similarly find evidence of spreading
dysfunction and pathology. One mechanism to account for this spread of disease
from one neural structure to another is by evoking prion-like propagation of a
toxic misfolded protein from cell to cell. Recent studies in animals that model
aspects of Alzheimer’s Disease, Parkinson’s Disease, and Tauopathy, have
bolstered the arguments in favor of prion-like, although in most of these models
the mice do not develop overt “clinical” symptoms. Recently, Jacob Ayers
demonstrated that the symptoms of ALS can be transmitted from a strain of mice
that expresses mutant SOD1-G93A at high levels to a second transgenic strain
that expresses mutant SOD1 at low, nontoxic, levels. This model showed many
prion-like features including evidence of host-adaptation (earlier and more
penetrant disease upon second passage). Interestingly, homogenates from
paralyzed mice expressing the G37R variant of SOD1 transmitted poorly, a finding
suggestive that different SOD1 variants may exhibit strain-like properties.
These “ i n d u c i b l e ” m o d e l s o f h u m a n neurodegenerative disease
enable the generation of models that do not require extraordinary levels of
transgene expression and provide a more precise means of initiating the disease
process, advances that may translate into more predictive pre-clinical
models.
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P188 Transmission of amyloid pathology by peripheral administration of
misfolded Aβ
Javiera Bravo-Alegria1 ,2, Rodrigo Morales2, Claudia Duran-Aniotz3, Claudio
Soto2 1University of Los Andes, Santiago, Chile, 2Mitchell Center for
Alzheimer’s Disease and Related Brain Disorders, Department of Neurology,
University of Texas Medical School, Houston, Texas, USA, 3University of Chile,
Santiago, Chile
Misfolding and aggregation of Amyloid-β (Aβ) is one of the primary events
involved in the pathogenesis of Alzheimer's disease (AD). Recently, it has been
proposed that Aβ aggregates can transmit and spread the pathology following a
prion-like mechanism. Prions can be exogenously transmitted by many different
routes of administration. In the case of Aβ, previous studies showed that
intraperitoneal (i.p.) injection of seeds can accelerate cerebral amyloidosis in
mouse models. However, other potential routes have not yet been studied. The
goal of this work was to assess whether Aβ amyloidosis can be seeded in the
brain of a transgenic mouse model of AD by peripheral administration of
misfolded particles.
Young tg2576 animals (50 days old) were inoculated with a pool of brain
extract coming from old Tg2576 animals (10%w/v) by different routes: i.p.
(100μL), eye drops (5μL each eye, 3 times), intramuscular (i.m., 50μL), and per
os (p.o., 1000μL). Animals were sacrificed at 300 days old, and brain samples
were analyzed for amyloid pathology by IHC and ELISA.
The i.p., i.m., and eye drops administration of Aβ seeds significantly
accelerated pathological features in tg2576. Regardless of the higher volume
administered, p.o. treated animals did not show any pathological changes when
compared to untreated controls. Differences in the proportion of diffuse, core
and vascular deposition was observed within experimental groups. Our data show
that peripheral administration of Aβ seeds could accelerate pathological changes
in the brain and suggest that an orchestrated cross-talk between the brain and
peripheral tissues occurs in AD.
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Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease
Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014
*** Singeltary comment ;
TSS
