eBook: Advancing Neuroscience Research - 14

endogenous tau to adopt misfolded conformations.5,6
After
internalization of tau PFFs, intracellular
fibrilization of endogenous tau was induced.
After recruitment, tau aggregates are externalized
through degenerating axons or somatodendritic
compartments via secretion or other undiscovered
mechanisms. The externalized tau aggregates are
then adopted by surrounding or interconnected
neurons, sustaining the theorized template for the
propagation of tau pathology. In contrast to cellbased
models, animal-based tau PFF models have
proven to be more of a challenge to establish. Injection
of heparin-induced wild-type tau-441 PFFs
were found to have a limited seeding capacity and
instead, require the combination of transgenic mice
and truncated tau-PFFs to achieve AD-like protein
aggregations. In one study, in vivo studies were established
through the hippocampal or frontal cortex
injection of truncated tau PFFs into tau Tg mice
expressing human mutant P301L tau.7
Through
the combination of both transgenic mouse and
PFF models, both induction of tau fibrillization
and spreading of tau pathology to interconnected
brain regions was observed. Neuronal loss in hippocampus
was observed, leading to the discovery
Figure 5. α-Syn immunostaining of substantia nigra pars compacta
of mice following intrastriatal PFF injection. Lewy-body
like inclusions (black arrows) were observed in ipsilateral sections
but were not observed in contralateral sections; this supports
the theory of a cell-to-cell transmission method for Lewy-bodies
composed of misfoldedα-syn. Reproduced from Luk 2012.11
of a new in vivo model for tau pathological spread
with neurodegeneration.
In PD, α-syn PFF models are commonly used to model
the two major disease processes: accumulation
of intraneuronal Lewy-bodies/neurites and selective
degeneration of midbrain dopamine neurons.
Whereas tau PFFs struggle to induce protein aggregations
in vivo, α-syn PFF models have been well-established
in both in vitro and in vivo. In vitro models
have been well established targeting primary neurons,8
human
iPSC-derived dopaminergic neurons,9
and organ-on-a-chip,10 all of which serve as efficient
tools for high-throughput drug screening and testing.
Similarly, α-syn PFFs efficiently seed aggregation
and fibrillization of endogenous α-syn in wildtype
mice. In one study, α-syn PFFs were injected,
targeting the dorsal striatum, which resulted in the
identification of hyperphosphorylated deposits of
α-syn.11
After 30 days post-injection, the Lewy-body
Figure 4. Nissl staining of the hippocampus of P301L mice
injected with buffer or truncated tau PFFs. AT8 (green, identifier
of tau-presence) was apparent in mice treated with
PFFs and shown to preceed neuronal loss found in the 3
month post-injection mice. Reproduced from Peeraer 2015.7
like accumulations traveled along the inter-neural
connectivity, suggesting a cell-to-cell transmission
method. Clinical symptoms related to PD were also
observed, including impaired balance and motor
coordination. Overall, a single intra-striatal injection
of misfolded α-syn PFFs was sufficient to initiate the
neurodegenerative cascade associated with PD, including
Lewy-body pathology, dopaminergic neuron
loss, and impaired motor function.
14
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