Relationships between misfolded proteins and brain diseases remain unclear. Protein
aggregates may accumulate in the central nervous system for years, probably decades,
before the onset of overt illness and during the slow progression of various common
neurodegenerative diseases. The protein aggregates may produce different pathologic
effects at different stages of disease[1 ],[2 ]. Typical intracellular inclusions or extracellular deposits of proteins are commonly
used to define specific neurodegenerative diseases. For example: β-amyloid (Aβ) plaques
and neurofibrillary tangles composed of hyperphosphorylated tau (p-tau) both accumulate
in Alzheimer's disease (AD), abnormal prion protein (PrPTSE ) in transmissible spongiform encephalopathies (TSEs, prion diseases), and intracellular
deposits of α-synuclein form Lewy bodies in Parkinson's disease (PD)[3 ],[4 ]. However, more than one protein can interact, modifying the pathogenesis of disease
by targeting different anatomical areas or altering signaling pathways in the brain.
For example, the merging of Aβ, normal cellular PrP (PrPC ) and the nonreceptor tyrosine kinase Fyn on lipid rafts may result in synaptotoxicity[5 ]. Fyn associates with tau, sensitizing synapses to glutamate excitotoxicity[6 ]. These studies led to the hypothesis that the association between PrPC and Fyn may couple Aβ and tau pathologies[6 ]. Tau and α-synuclein each promote aggregation of the other protein[7 ], while Aβ seems to promote hyperphosphorylation of tau by downregulating the insulin
signaling pathway[8 ]. Recent studies expanded this concept by showing that pre-aggregated Aβ can serve
as a template that aggregates filamentous tau by cross-seeding[9 ]. While the interactions of normal endogenous proteins of the central nervous system
are complex and poorly understood, certain common pathways appear to be activated
in different neurodegenerative diseases[10 ]. The neuropathologic analysis of dementing diseases has become increasingly important:
(i) clinical signs sometimes reflect the neuroanatomical distribution of lesions but
do not necessarily predict specific histopathologic and biochemical alterations; (ii)
development of new diagnostic tests and effective therapies require postmortem validation;
(iii) increased prevalence of dementia in an aging population makes it a priority
for clinical medicine, healthcare and social support systems as well as for research;
and (iv) diagnosis of dementing diseases often comes late in the course of the disease
when brain damage is already severe and irreversible so that therapy is likely to
offer little or no benefit. Taken together, these considerations affirm the need to
study accessible markers of neurodegeneration in young populations and in healthy
neurological controls. Clinico-pathologic and imaging studies have shown that some
people without dementia have substantial AD pathology in the central nervous system[11 ]. Recently, Perez-Nievas and colleagues found that Aβ plaques and neurofibrillary
tangles did not always correlate with dementia; they identified glial activation as
a more likely mediator of neurotoxicity[11 ]. In conclusion, the study of autopsy cases remains necessary to confirm antemortem
clinical and neuroimaging diagnosis, to define new disease phenotypes, to assess the
specificity and sensitivity of antemortem diagnostic tests and to evaluate the effects
of potential therapeutic interventions. However, in an era when autopsies are no longer
common—even in academic settings—ambitious programs to investigate postmortem findings
in familial and sporadic neurodegenerative diseases face obvious challenges not discussed
further in this review. Fortunately, recent technological advances using transgenic
animals, proteomics and experimental immunohistopathology have allowed development
of sophisticated experimental models to study neurodegenerative diseases associated
with protein misfolding[12 ].
ANIMAL MODELS
Animal models that recapitulate the pathogenesis of the human diseases AD, PD, and
TSEs are especially needed to improve the understanding of chronic neurodegeneration.
Only one group of human neurodegenerative diseases has been convincingly modeled in
experimental animals: the TSEs or prion diseases[13 ]. Human prion diseases are unique because they occur in idiopathic (sporadic), familial
and acquired forms. In humans, the most common TSE is sporadic Creutzfeldt-Jakob disease
(CJD). Several other prion diseases have been described in farmed and wild animals:
scrapie in sheep and goats, chronic wasting disease in deer and other cervids, bovine
spongiform encephalopathy (BSE) and its feline derivative, transmissible mink encephalopathy
and, most recently, a TSE of camels[14 ]. Animal models of prion diseases have been used to study neurodegeneration because
they so closely resemble the human TSEs, are highly reproducible, and express several
informative phenotypes. No transgenic-mouse model of AD, PD or the tauopathies so
closely resembles the sporadic human neurodegenerative diseases[13 ].
Animals with TSEs develop many neuropathologic hallmarks of other neurodegenerative
diseases, e.g., protein accumulation, synaptic degeneration and neuronal loss, severe
microgliosis and astrogliosis. Animal models can be precisely monitored from the time
the agent is inoculated through advanced illness, facilitating study of both latent
and overt phases of disease. We have shown that amyloid plaques containing PrP can
form in mouse brains in the absence of infectivity detectable by inoculation of highly
susceptible animals, suggesting that not all misfolded PrP is infectious in these
experimental paradigms[14 ],[15 ],[16 ],[17 ]. Thus, proteinopathies sharing some similarities to AD and PD occur in brains of
mice when PrP misfolds. First, we review recent data from experimental TSEs of nonhuman
primates and mice; next we summarize data from a recently-reported natural complex
proteinopathy of bovines (not caused by BSE or another TSE), the first tauopathy described
in ruminants[18 ].
Primates inoculated with classical BSE agent (SQ-BSE) develop a vCJD-like disease
All primate tissues examined and described in this review were produced in previously-described
transmission experiments[19 ]. All experiments were reviewed and approved by the Institutional Animal and Care
Committee of the Center for Biologics, Evaluation and Research, of the US FDA. We
infected squirrel monkeys (Saimiri sciureus ) with the agent of classical bovine spongiform encephalopathy (SQ-BSE). Most animals
(6/7) inoculated with a low dilution of BSE-infected bovine brain (generously provided
by Torsten Seuberlich, University of Bern, Switzerland) became ill; two to four years
later those animals developed cognitive and behavioral alterations with other neurological
signs (tremors, bradykinesia, myoclonus, ataxia) typical of prion diseases. At necropsy,
the brains from all sick monkeys showed pathological changes similar to those described
in humans with variant Creutzfeldt-Jakob disease (vCJD)—a zoonosis transmitted to
humans who ate meat or meat products from animals with BSE** (**A few cases of vCJD
were transmitted by transfusion of red blood cells and injections of a human plasma
product prepared from donations by otherwise healthy blood donors presumed to have
been silently incubating vCJD)[19 ]. All sick monkeys showed histopathological features typical of spongiform encephalopathy:
widespread, severe astrogliosis, and accumulations of PrPTSE in the cerebrum and cerebellum. There were no “florid” plaques (amyloid PrP-containing
plaques surrounded by halos of vacuoles); such plaques have been a consistent, although
not specific, feature in brains of patients with vCJD. Interestingly, florid plaques
have never been observed in brains of cows with BSE, showing that the host determines
some neuropathologic features of a TSE. Western blot analyses of brain homogenates
from the six monkeys with disease confirmed that they all contained proteinase-K resistant
PrP (PrPTSE )[19 ],[20 ].
Brains of monkeys with SQ-BSE show severe tauopathy and synaptic pathology without
Aβ deposits
Brain tissue sections were probed with a panel of anti-tau antibodies (AT8 [Ser202/Thr205],
AT100 [Ser212/Thr205], AT180 [Thr231], AT270 [Thr181]) that bind to hyperphosphorylated
tau (p-tau) and with an antibody to four-repeat tau isoforms [RD4]). The brains of
all six monkeys with neurological signs and histopathology of TSE ([Figure A, B, D, E, J, K ]) showed identical tau-positive immunostaining patterns with abundant round and rod-shaped
aggregates of positive-staining material ([Figure G, H ]). These lesions did not resemble the typical p-tau deposits seen in AD or tauopathies
(i.e., neurofibrillary tangles, neuropil threads or diffuse intracytoplasmic staining
([Table ]; [Figure G, H ]). Positive tau staining was seen in the cerebral cortex, thalamus, hypothalamus,
hippocampus, cerebellum and brain stem. The extensive accumulations of p-tau observed
in the molecular, Purkinje and granule cell layers of the cerebellum were unexpected.
This finding shows that the cerebellum, (an anatomical region of the central nervous
system previously considered refractory to tau pathology in humans) was targeted in
an experimental encephalopathy accompanying PrP accumulation. The last squirrel monkey
to become ill after an incubation period of approximately 8 years, SQ-736, showed
more severe spongiform degeneration, PrPTSE , p-tau and astrogliosis than SQ-735 (after an incubation period of 3.2 years) inoculated
with the same dose of BSE agent ([Figure ]). Similar patterns and distribution of PrPTSE and p-tau-containing lesions were seen with all anti-PrP and anti-tau antibodies
used[21 ]. The areas most affected were the frontal cortex and thalamus.
Figure Squirrel monkeys (SQ) inoculated with classical BSE (SQ-BSE) develop TSE and a complex
proteinopathy. (A, D, G, J) SQ-BSE 735 with incubation period of 3.2 years; (B, E,
H, K) SQ-736 with incubation period 8.1 years; (C, F, I, L) SQ-718 (control) with
no TSE confirmed neuropathologically. Moderate (A) and severe (B) spongiform degeneration,
brain tissue sections stained with hematoxylin-eosin (HE). Moderate (D) and severe
(E) PrPTSE accumulation in the neuropil. Moderate (G) and severe (H) p-tau immunopositivity
in adjacent sections of the frontal cortex. Moderate (J) and severe (K) astrogliosis
in the same region of the neocortex. (C, F, I, L) No spongiform degeneration, PrPTSE , p-tau or astrogliosis are seen in the frontal cortex of SQ without TSE. (A-C) HE;
(D-F) PrP (antibody 6H4); (G-I) p-tau (antibody AT8); and anti-glial fibrillary acidic
protein antibody (J-L). All panels 40x magnification.
Table
Neuropathologic characterization of rodents and bovines with tauopathy.
IP (days)
p-tau
SD
PrPTSE
α-syn
Ub
Aβ
Bov6.H.BSE
590
+
+
+
NA
NA
NA
Bov6.C.BSE
540
+
+
+
NA
NA
NA
Bov6.BASE
635
+
+
+
NA
NA
NA
87V/VM
320
+
+
+
NA
NA
NA
ME7/C57
160
+
+
+
NA
NA
NA
GSS22
198
_(#1)
+
+
NA
NA
NA
101LLrec.PrP-101LL
NA
_
_
+
NA
NA
NA
101LL rec.PrP-Wt
NA
_
_
+
NA
NA
NA
IBNC
NA
+
+
+
+
+
_
SQ-BSE
870-2960
+
+
+
+
+
_
IP: incubation period; p-tau: hyperphosphorylated tau detection by immunohistochemistry
(IHC) with antibody AT8 (epitope human tau protein Ser202/Thr205); SD: spongiform
degeneration; α-syn: α-synuclein detection by IHC (immunogen recombinant human α-synuclein);
Ub: ubiquitin detection by IHC with antibody Ubiquitin-1 (raised against purified
ubiquitin conjugated with glutaraldehyde to keyhole limpet hemocyanin).
(#1)Minimal p-tau immunopositive deposits were observed in one animal.
H.BSE: heavy (H-type) bovine spongiform encephalopathy (BSE); C.BSE: classical BSE;
BASE: bovine amyloidogenic spongiform encephalopathy (light, or L-type BSE); IBNC:
idiopathic brainstem neuronal chromatolysis; SQ-BSE: squirrel monkey classical BSE
The temporal cortex was spared, showing no spongiform degeneration, severe gliosis
or PrP deposits; no obvious accumulation of p-tau was seen. To explore another marker
of neurodegeneration—the synaptic pathology observed in early stages of TSEs and other
neurodegenerative diseases[22 ]—we probed tissue sections with antibody to synaptophysin (Abcam, Cambridge, MA),
a component of the membrane glycoprotein of synaptic vesicles that serves as a marker
of presynaptic terminals. Synaptophysin, in the form of fine granular and evenly distributed
deposits (as seen in preserved brain sections), was significantly reduced in all brain
areas containing protein deposits and astrogliosis but remained unaffected in the
temporal cortex, confirming that neurodegenerative histopathology was not evenly distributed.
The p-tau deposits did not have the morphologic features of neurofibrillary tangles,
neuropil threads, or diffuse intracytoplasmic tau described in some human patients
with dementia[23 ]. Brain sections from a control animal without prion disease showed no evidence of
TSE, and p-tau deposits were completely absent ([Figure C, F, I, L ]). Sections probed with 4G8 antibody, directed to amino acid residues 17-24 of β-amyloid
(commonly used to detect Aβ in humans with AD, in animal models of AD and in nondemented
persons with Aβ deposits[24 ],[25 ]), showed no immunostaining in the brain of any animal with prion disease. Adjacent
sections treated with Congo red dye showed no congophilia and no birefringence under
polarized light (confirming the absence of amyloid deposits). In short, all monkeys
with BSE developed severe spongiform encephalopathy with parenchymal accumulations
of PrPTSE and p-tau in the cerebrum, cerebellum and brain stem. The areas most severely affected
were the frontal cortex and thalamus, but no amyloid protein of any kind was observed
in any of these animals.
Accumulation of α-synuclein and ubiquitin in SQ-BSE
To complete the neuropathologic characterization of SQ-BSE, we probed brain sections
with antibodies to apolipoprotein-E, a risk factor for late-onset AD (also influencing
Aβ and tau formation), to α-synuclein (present in Lewy bodies in PD), ubiquitin (a
major component of the proteolytic quality control system), and synaptophysin (see
above). In addition, we examined formalin-fixed samples of spleen, liver and kidney[21 ]. Analysis of adjacent brain tissue sections showed that PrPTSE (mostly as coarse pericellular aggregates), p-tau (rod-shaped), α-synuclein (small
punctate) and ubiquitin (small punctate) were deposited mainly in the neuropil of
areas with severe spongiform degeneration; deposits were also prominent at the periphery
of vacuoles; no PrPTSE was observed in peripheral organs[21 ]. The brains of all six monkeys contained more PrPTSE than p-tau or α-synuclein. Similar observations in human cases and in some other
animal models have led others to suggest that the dose-dependent toxicity triggered
by PrPTSE might be the primary cause of neurodegeneration[26 ]. Further studies will be needed to explore a possible role for other factors, such
as inflammation, in TSE pathogenesis.
P-tau in rodents with PrP accumulation
To explore further the association between p-tau and PrP while eliminating the potential
confounding effects of aging, unrelated diseases, drug treatment, agonal changes and
postmortem delay inevitable in human autopsy cases and to expand the study from nonhuman
primates to small animals, we analyzed several murine models. All rodent tissues examined
and described in this review were produced in previous transmission experiments[27 ],[28 ],[29 ],[30 ],[31 ] performed under licence from the UK Home Office in accordance with the Animals (Scientific
Procedures) Act 1986. The severe tauopathy seen in squirrel monkeys infected with
classical SQ-BSE[19 ] led us to study a line of transgenic mice from which the murine PRNP gene was deleted and then engineered to express a bovine PrP with a six-octapeptide
repeat region (“bovinized knock-in” B6 mice)[28 ]; we analyzed B6 mice intracerebrally inoculated with classical BSE agent from a
bovine brain and also analyzed B6 mice inoculated with brain suspensions from cattle
with two atypical forms of BSE: “heavy” or H-type BSE and bovine amyloidogenic spongiform
encephalopathy (also called “light” or L-type BSE)[29 ]. To study possible correlation between PrP amyloid and p-tau, we used the following
models: (i) wild-type (Wt) VM mice (an inbred Wt line of mice with known susceptibility
to scrapie) inoculated intracerebrally with 87V mouse-adapted scrapie agent (87V-VM)[30 ],[32 ]; (ii) transgenic mice overexpressing mutant PrP-101L (equivalent to a mutation found
in Gerstamann-Sträussler-Scheinker disease, GSS-22) that spontaneously develop a severe
spongiform degeneration with abundant diffuse and amyloid PrP deposits in most areas
of the central nervous system[17 ],[27 ]; and (iii) knock-in mice expressing a murine mutant PrP (101LL, corresponding to
human PRNP P102L) inoculated with recombinant wild-type PrP (recWt-PrP) or recombinant mutant
PrP (recPrP-101L) fibrils[33 ]. To study p-tau accumulation in animals with large amounts of widespread diffuse
nonamyloid PrPTSE deposits, we inoculated Wt C57BL mice with ME7 mouse-adapted scrapie agent (ME7-C57BL)[30 ]. Uninoculated mice of the same types described above served as normal controls.
Similar tauopathy seen in PrP-bovinized mice infected with agents from typical and
atypical forms of BSE
Similar patterns and distribution of p-tau were seen in brains of B6 mice inoculated
with BSE agents of all three types: classical, H-type, and L-type[31 ]. The largest amounts of p-tau were observed in the brains of B6 mice inoculated
with L-BSE agent. In the brains of mice inoculated with BSE agents all three types,
the cerebral cortex was consistently affected. Confocal microscopic images of isolated
p-tau deposits showed that PrPTSE co-localized with p-tau; Imaris 3D reconstruction confirmed that observation and
revealed p-tau deposited throughout PrP plaques in classical BSE and H-type BSE as
well. No p-tau was detected in brain sections of uninoculated age-matched control
B6 mice probed with anti-tau antibodies (AT8 or Thr231) or in BSE-infected B6 mice
incubated without primary antibody. In short, p-tau accumulated widely in the brains
of B6 mice infected with both typical and atypical BSE agents[31 ] ([Table ]) in the same places as PrPTSE deposits.
P-tau in wild-type mice inoculated with mouse-adapted ME7 and 87V scrapie agents
The strains ME7 and 87V are mouse-passaged scrapie agents that elicit disease after
very different incubation periods: 160 days for ME7 in C57BL mice and 320 days for
87V in VM mice. The two models also have distinct histopathologies[30 ]. The brains of terminally ill C57BL mice infected with ME7 scrapie showed severe
gliosis and accumulated large amounts of diffusely distributed PrPTSE with only small numbers of amyloid plaques. In contrast, the brains of VM mice infected
with 87V scrapie contained abundant amyloid plaques and both coarse and fine-punctate
deposits of PrPTSE . Brains of terminally ill C57BL mice infected with ME7 scrapie contained small amounts
of p-tau in most areas with spongiform degeneration[31 ]. The brains of terminally ill VM Wt mice infected with 87V scrapie contained deposits
of p-tau within and adjacent to the margins of PrPTSE amyloid plaques; p-tau was also observed in the same regions where diffuse nonamyloid
PrPTSE deposits occurred[31 ] ([Table ]). Confocal and Imaris 3D reconstruction of double-labeled sections showed that p-tau
colocalized with PrPTSE aggregates throughout the plaques in both 87V/VM and ME7/C57 models. In short, two
mouse-adapted scrapie strains elicited widespread formation of p-tau in multiple brain
areas in two lines of inbred Wt mice; 87V scrapie infection of VM mice induced the
largest amounts of p-tau in the cerebral cortex, deposited in the same areas containing
PrP-amyloid. In a time course study, PrPTSE deposits in the brain preceded the appearance of p-tau in both animal models. Others
have reported similar results[26 ].
Over expression of mutant PrP and neurodegeneration in mouse brains was not accompanied
by accumulation of p-tau
Mice overexpressing PrP-P101L (GSS-22 mice)[27 ] have spontaneously developed severe spongiform degeneration accompanied by large
numbers of PrP amyloid plaques and widespread gliosis in the brain. Although GSS-22
mice expressed a neurological disease with all the hallmarks of a spongiform encephalopathy,
suspensions of their brains have not transmitted prion disease to either Wt or 101LL
mice and therefore appear to be devoid of infectivity. The GSS-22 mice provide a model
to study possible correlations between PrP aggregates and p-tau in animals that express
mutant PrP throughout their lifespan but are not exposed to the trauma of intracerebral
inoculation and do not develop a transmissible disease. We observed that, despite
the severe spongiform degeneration and accumulation of large PrP plaques in their
brains at terminal disease, these animals had almost no p-tau in any brain areas ([Table ]). Confocal microscopy confirmed this unexpected finding. Similar results were obtained
in sections probed with either of two antibodies to p-tau: AT8 and Thr231. In short,
we observed almost no p-tau in any brain areas at terminal disease.
Brains of animals inoculated with recombinant PrP accumulated PrP-amyloid without
detectable p-tau
To develop a model of seeded PrP proteinopathy, we inoculated synthetic PrP amyloid
fibrils into PRNP -knock-in mice homozygous for a proline-to-leucine mutation at PrP codon 101 (101LL
mice); the amyloid fibrils were composed of either wild-type recombinant PrP (recWt-PrP)
or mutant recombinant PrP (rec101L-PrP)[33 ]. The inoculated 101LL mice developed no overt signs of prion disease, no histopathological
spongiform degeneration of the brain, and had no replication of infectivity as evidenced
by failure to transmit any illness (overt or histopathological) to 101LL mice; the
inoculated 101LL mice did, however, accumulate large PrP amyloid plaques in and adjacent
to the area of inoculation (in corpus callosum and hippocampus), but no p-tau was
detectable by immunolabeling with anti-tau antibodies AT8 and Thr231[31 ] ([Table ]). This model is important because it eliminated possible artifacts resulting from
(i) overexpression of PrP (since PrP expression levels were normal), (ii) pathology
resulting from a replicating infectious agent (because there was no demonstrable prion-related
infectivity), or (iii) damage from spongiform encephalopathy (which was absent). In
addition, because we injected only synthetic recombinant PrP, there could be no effect—enhancing
or inhibiting—on formation of p-tau by any of the other molecules that inevitably
“contaminate” extracts of human or animal brains. In short, although we found that
p-tau co-localized with PrPTSE amyloid plaques in the brains of 87V-VM mice infected with a scrapie agent absence
of p-tau in the brains of 101LL mice inoculated with recombinant PrP fibrils shows
that PrP amyloidogenesis alone does not invariably lead to formation of p-tau in the
brain.
Natural tauopathy in ruminants
Idiopathic brainstem neuronal chromatolysis (IBNC) is a neurological disease first
recognized in 1986 in the UK among some adult cattle slaughtered because of suspected
BSE[18 ]. The clinical presentation of IBNC includes behavioral and locomotor changes[18 ]. This disorder is characterized neuropathologically by neuronal chromatolysis and
degeneration in the brainstem plus hippocampal sclerosis and spongiform changes in
the gray matter of the cerebrum[18 ]. Investigations of possible causes of IBNC included testing for viruses and for
deficiencies in vitamins, trace elements and minerals; all results were negative.
Abnormal PrP was detected in the brains of several IBNC cases[18 ]; however, IBNC was not successfully transmitted to transgenic mice expressing a
bovine PrP gene[18 ]. Recently, we performed an immunohistochemical analysis of brains from 15 bovines
with IBNC, looking for accumulations of several important proteins[34 ]. Brain sections from all animals, probed with six different anti-tau antibodies
directed against hyperphosphorylated serine or threonine phospho-epitopes, showed
positive staining of astroglia in gray and white matter, dendrites and neuronal cell
bodies ([Table ]). The most intense p-tau staining was seen in cases with severe spongiform degeneration;
however, p-tau was not observed in chromatolytic neurons. P-tau was detected in the
cerebrum, gray matter nuclei of the neuroaxis, and cerebellum. P-tau-positive structures
also contained ubiquitin and α-synuclein but not Aβ peptide. Alpha-synuclein labeling
was conspicuous in the dentate gyrus and surrounding dendrites of the substantia nigra,
globus pallidus and entorhinal cortex. It has been proposed that the pattern of α-synuclein
accumulation in IBNC resembles that occurring secondary to synaptic loss in human
brains, rather than resulting from a primary accumulation of abnormal α-synuclein[34 ]. Punctate staining of ubiquitin was also seen, mostly in the cerebral cortex, hippocampus,
thalamus, white matter and brain stem, largely in the same areas with hyperphosphorylated
tau deposits. The brains of age-matched control cattle were negative when stained
with antibodies against all the proteins studied. In conclusion, the neuropathology
of IBNC did not correspond to any complex proteinopathy described in humans. While
the etiology of IBNC remains unknown, results of epidemiological and experimental
studies so far suggest that it is unlikely to result from an infection. Environmental
factors, including exposure of cattle to agricultural chemicals, should be investigated.
Conclusion
In the experimental models described above (SQ-BSE, B6-BSE, ME7/C57, 87V/VM) complex
protein aggregates containing both PrPTSE and p-tau were evident when disease was transmitted to susceptible recipient animals
and serially passaged (i.e., was confirmed to have an infectious mechanism). In contrast,
in the other animal models, p-tau was never observed in animal brains containing misfolded
PrP when no infectious agent was detected (rec101LL, rec101Wt). Therefore, it is evident
that p-tau accumulated only in brains containing both misfolded PrP and infectivity
and not in brains with misfolded PrP alone. One possible explanation is that replication
of infectivity plus host factors together elicit the formation, deposition and aggregation
of heterogeneous protein, including p-tau, in the brain.
In aged cattle, IBNC is characterized by widespread deposits of p-tau in most areas
of the brain, the rare example of a naturally-occurring tauopathy in a nonprimate
species. Idiopathic brainstem neuronal chromatolysis is the first tauopathy of ruminants
in which α-synuclein and ubiquitin also accumulate. While the etiology of IBNC is
unknown, its occurrence in several breeds of cattle argues against a genetic etiology.
This disease has not been transmitted experimentally (M. Stack, personal communication)[34 ], leading to a preliminary conclusion that environmental exposures are more likely
than infection to cause IBNC.
Several age-related neurodegenerative diseases are associated with the accumulation
of specific proteins in the nervous system. Protein aggregates clearly induce the
misfolding of similar proteins to form characteristic lesions. The apparent simplicity
of this molecular process and consistency in histopathology contrast dramatically
with the remarkable clinical-pathological heterogeneity seen in patients with Alzheimer's,
Parkinson's, and prion diseases. New data suggest that this variability may be mediated
by the formation of diverse protein architectures referred to as “proteopathic strains”[35 ]. In turn, such proteopathic strains could be influenced by genetic, cellular/post-translational
and environmental factors. We and others suspect that the genesis of complex proteinopathies
may also involve participation of other molecules (e.g., heparan sulfate proteoglycan[31 ],[36 ]). Transcellular propagation of protein aggregates has been proposed to mediate neurodegeneration.
Glycosaminoglycans are required for cellular uptake of tau, α-synuclein and β-amyloid
proteins. Stopschinski et al. recently reported considerable specificity for interaction
of aggregated tau protein with glycosaminoglycans, while the interaction of α-synuclein
and β-amyloid is less stringent[36 ]. These findings might explain some of the phenotypic heterogeneity so characteristic
of the histopathology in the brains of humans with age-related neurodegenerative diseases.
A better understanding of these factors and their interactions should improve our
knowledge of disease processes, lead to development of new diagnostic methods, and
even suggest new targets for therapy. Continued study of animal models will support
those efforts.
