Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model

p301L tau mice exhibit well-characterized age-dependent increases in neuronal tau pathology within cell bodies, dendrites and axons, mimicking pathology observed in AD.

“Mice expressing the mutant variant exhibit well characterized age-dependant increases in neuronal tau pathology within cell bodies, dendrites and axons mimicking pathology observed in AD 23.”

• cites [23] Guo, 2004, Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease, Am. J. Pathol. sourceCould not verify

  The Tissue Collection and Characterization section describes human AD and control brains, and Results and Discussion reports tau pathology in those brains. Our copy does not address P301L tau mice or age-dependent changes in their cell bodies, dendrites, and axons (searched: P301L tau transgenic mice; mutant tau mice age-dependent pathology). (LLM, conf=0.77)

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Previous work from the authors' lab found no axonal damage in the optic tract or optic nerves after Aβ injection into the LGN of wild type mice.

“Our lab previously has explored the degeneration induced by an Aβ injection in LGN of wild type mice, and we did not find axonal damage in optic tract or optic nerves 29”

• cites [29] Kantarci, 2017, White-matter integrity on DTI and the pathologic staging of Alzheimer's disease, Neurobiol. Aging sourceCould not verify

  The Introduction describes a study of DTI findings in older adults followed to autopsy, not Aβ injections in wild-type mice. Searches for LGN injections, optic tracts, optic nerves, and axonal damage found no passage in our copy reporting the claimed experiment or its result. (LLM, conf=0.76)

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EpoD at 1 mg/kg was sufficient to reduce measures of tauopathy, neurodegeneration and axonal dystrophy in PS19 tau mice in previous work.

“The dose for this experiment was chosen based upon previous work by Brunden et. al. and Zhang et. al. in which EpoD at 1mg/kg was sufficient to reduce measures of tauopathy, neurodegeneration and axonal dystrophy in PS19 tau mice 30, 31.”

• cites [30] Kastyak-Ibrahim, 2013, Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice, Magn. Reson. Imaging sourceNot checked — no full text of the source
• cites [31] Kneynsberg, 2017, Axonal degeneration in tauopathies: disease relevance and underlying mechanisms, Front. Neurosci. sourceCould not verify

  The Animal models of tauopathies section discusses axonal pathology in transgenic mice, but not EpoD treatment. Searches of the full-text copy for EpoD, epothilone, PS19, Brunden, and the 1 mg/kg dose found no passage reporting the attributed treatment result; the paper’s References section does not establish it either. (LLM, conf=0.76)

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Evidence from AD tissue suggests early axonal dysfunction precedes overt cell loss, including dystrophic axons, dysfunctional axonal transport and cytoskeletal abnormalities early in the disease process.

“This idea is bolstered by evidence from AD tissue, suggestive of early axonal dysfunction preceding overt cell loss. This includes the presence of dystrophic axons, dsyfunctional axonal transport and cytoskeletal abnormalities early in the disease process 62,63.”

• cites [62] Sun, 2015, Axonal terminals exposed to amyloid-beta may not lead to pre-synaptic axonal damage, J Alzheimers Dis sourcePartly supported

  The Introduction (page unavailable) describes early synaptic deficits before later neuronal loss and discusses axonal degeneration as a possible mechanism. It does not report dystrophic axons, dysfunctional axonal transport, or cytoskeletal abnormalities in AD tissue. Its own experiment was in mice, not AD tissue, and found no significant axonal damage after the tested exposure. (LLM, conf=0.86)

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• cites [63] Sun, 2017, Anterograde-propagation of axonal degeneration in the visual system of wlds mice characterized by diffusion tensor imaging, J. Magn. Reson. Imag. sourceCould not verify

  The Introduction and Discussion describe axonal degeneration after retinal ischemia in mice; the Discussion also mentions cytoskeletal disintegration in a rat model. Neither section reports findings from Alzheimer’s disease tissue or establishes that dystrophic axons, impaired axonal transport, and cytoskeletal abnormalities precede cell loss in that disease. Searches for those features and their timing yielded no supporting passage in our copy. (LLM, conf=0.76)

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Previous studies have shown that EpoD and NAP can reduce p-tau pathology in AD model mice over several months of treatment.

“Additionally, previous studies utilizing EpoD as well as microtubule-stabilizing peptide NAP have both shown ability to reduce p-tau pathology in AD model mice over several months of treatment 31,66,67”

• cites [31] Kneynsberg, 2017, Axonal degeneration in tauopathies: disease relevance and underlying mechanisms, Front. Neurosci. sourceCould not verify

  The Animal models of tauopathies section discusses tau pathology in mice, but not EpoD or NAP treatment. Searches of our copy for EpoD, NAP, and microtubule-stabilizing treatment found no passage reporting reduced phosphorylated-tau pathology after several months of treatment. (LLM, conf=0.74)

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• cites [66] van der Walt, 2013, Optic nerve diffusion tensor imaging after acute optic neuritis predicts axonal and visual outcomes, PLoS One sourceCould not verify

  The Discussion (page unavailable) concerns optic-nerve diffusion imaging after acute optic neuritis; its “AD” refers to axial diffusivity, not Alzheimer’s disease. Searches for EpoD, NAP, phosphorylated tau, and Alzheimer’s model mice found no passage addressing the claimed treatment effects. (LLM, conf=0.76)

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• cites [67] Vana, 2011, Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment and Alzheimer's disease, Am. J. Pathol. sourceCould not verify

  The paper describes tau pathology in human nucleus basalis tissue from people with no cognitive impairment, mild cognitive impairment, or Alzheimer’s disease. Searches for EpoD and NAP found no passage about either treatment reducing phosphorylated tau in AD-model mice over several months. (LLM, conf=0.75)

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Degeneration could be initiated through synaptic or axonal mechanisms, independent of apoptosis.

“These observations raise the prospect that degeneration could be initiated through synaptic or axonal mechanisms, independent of apoptosis, a mechanism which has been widely studied in other model systems, such as spinal cord injury and Multiple Sclerosis 59–61.”

• cites [59] Song, 2004, Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition, Neurobiol. Dis. sourceNot checked — no full text of the source
• cites [60] Stancu, 2015, Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice, Acta Neuropathol. sourcePartly supported

  The Discussion (page unavailable) reports impaired synaptic plasticity and points to a postsynaptic mechanism for tau-seeding-induced neuronal dysfunction. It does not establish that degeneration is initiated through synaptic or axonal mechanisms, or that the process is independent of apoptosis. (LLM, conf=0.83)

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• cites [61] Sun, 2005, Detection of age-dependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer's disease using magnetic resonance diffusion tensor imaging, Exp. Neurol. sourceNot checked — no full text of the source

Overexpression of NMNAT1 & 2, which delays axonal disruption propagating from a transaction site, is neuroprotective in tauopathy models.

“Notably, overexpression of nicotinamide mononucleotide adenylyl transferase 1 & 2 (NMNAT1 & 2), which delays the process of axonal disruption propagating from a transaction site, was found to be neuroprotective in tauopathy models 6465.”

• cites [64] Umahara, 2002, Demonstration and distribution of tau-positive glial coiled body-like structures in white matter and white matter threads in early onset Alzheimer's disease, Neuropathology sourceNot checked — no full text of the source
• cites [65] Uribe, 2012, Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice, Hum. Mol. Genet. sourceCould not verify

  The Results and Discussion passages concern protection from axonal degeneration through caspase-6 deficiency, not NMNAT1 or NMNAT2 overexpression. Searches for NMNAT overexpression, tauopathy models, and degeneration from a transection site found no passage addressing the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.75)

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In mouse models, reductions in AxD are seen during acute axonal degeneration.

“In mouse models, Reductions in AxD are also seen during acute axonal degeneration 25, 57.”

• cites [25] Ho, 2015, Investigating degeneration of the retina in young and aged tau P301L mice, Life Sci. sourceNot checked — no full text of the source
• cites [57] Soares, 2013, A hitchhiker's guide to diffusion tensor imaging, Front. Neurosci. sourcePartly supported

  The Application fields section says axial diffusivity is related to structural changes that can indicate axonal injury. It does not say that axial diffusivity decreases during acute axonal degeneration in mouse models; those condition, population, and direction details are unsupported by this source. (LLM, conf=0.82)

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Reductions in AxD are observed in human WM during acute injury settings, such as optic neuritis.

“Reductions in AxD is observed in human WM during acute injury settings, as in optic neuritis (inflammation/neurodegeneration of the ON) 56”

• cites [56] Singh, 2017, Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis, J. Neuroinflammation sourceCould not verify

  The Results sections describe histological measures of axonal damage in multiple sclerosis tissue and mouse EAE lesions, not reductions in AxD in human white matter during optic neuritis. Searches for axial diffusivity, AxD, and optic neuritis found no passage addressing the cited claim. (LLM, conf=0.76)

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EpoD co-treatment with Aβ significantly reduced p-tau pathology in the hippocampus compared to the Aβ-treated cohort (>80% reduction, p<0.01).

“significant (>80%, p<0.01) reductions in p-tau were apparent in the hippocampus, as compared with the Aβ-treated cohort (Figure 8c,f).”

Aβ injection into the left LGN of p301L tau mice resulted in significant reductions in fractional anisotropy (FA) asymmetry in the optic nerve at 8 weeks compared to vehicle controls (0.85±0.15 vs 1.06±0.13).

“eight weeks after injection, we found significant (p<0.01) reductions in FA asymmetry among Aβ-treated mice (0.85±0.15) vs. vehicle controls (1.06±0.13).”

OCT measurements of GCC thickness asymmetry revealed no significant differences between groups (Vehicle, Aβ or Aβ/EpoD treated) at baseline or after 1, 4 or 8 weeks.

“OCT measurements of GCC thickness asymmetry revealed no significant differences between groups (Vehicle, Aβ or Aβ/EpoD treated) at baseline or after 1, 4 or 8 weeks (Figure 4).”

In 3-month p301L mice, EpoD significantly reduced p-tau pathology relative to mice receiving Aβ treatment alone.

“EpoD significantly reduced p-tau pathology, relative to mice receiving Aβ-treatment alone (Figure 9d).”

Aβ injection into the left LGN of p301L tau mice resulted in significant reductions in axial diffusion (AxD) asymmetry in the optic nerve at 8 weeks compared to vehicle controls (0.817±0.098 vs 1.01±0.13).

“after eight weeks we observed significant reductions in AxD asymmetry among Aβ-treated mice (0.817±0.098) vs. vehicle controls (1.01±0.13, p<0.05)”

Aβ injection into the left LGN of p301L tau mice resulted in significant reductions in SMI31 axon labeling in the optic tract at 8 weeks compared to vehicle controls (0.82±0.087 vs 0.98±0.085).

“Measurements of SMI31 intensity asymmetry (Aβ-affected side vs contralateral side) in OT revealed significant reductions in axon labeling among Aβ-injected mice (0.82±0.087), relative to vehicle controls (0.98±0.085, Figure 6a).”

No significant differences in p-tau axon density were found between left and right optic nerves in Aβ-injected and vehicle-treated mice.

“we found no significant differences in p-tau axon density between left / right ONs in Aβ-injected and vehicle-treated mice (Figure 8d).”

Aβ injection into the left LGN of p301L tau mice resulted in loss of synapses in the injected LGN at 8 weeks, as shown by reduced Synapsin-1 labeling.

“obvious reductions in Synapsin-1 (syn-1, a marker of presynaptic terminals labeling) were apparent in the injected LGN, relative to the contra-lateral side”

No significant relationships were observed between myelin staining and DTI measures.

“No significant relationships were observed between myelin staining and DTI measures.”

No significant correlations were found between axon losses and density of AT8+ axons.

“we found no significant correlations between axon losses and density of AT8+ axons (Figure 8e).”

EpoD pretreatment prevented the acute Aβ-induced increases in p-tau in the LGN and hippocampus.

“However, these increases in p-tau were not seen in mice pretreated with both Aβ/EpoD.”

p301L mice exhibited robust pathological tau deposition in the visual system at 10 months of age.

“However, we only found robust exhibition of pathological tau deposition in the visual system later at 10 months of age.”

Aβ injection into the left LGN of p301L tau mice resulted in significant reductions in axon number asymmetry in the optic nerve at 8 weeks compared to vehicle controls (0.71±0.22 vs 0.98±0.09).

“Within the ON, we found significant reductions in axon number asymmetry in Aβ-treated mice (asymmetry = 0.71±0.22), compared with vehicle-treated mice (0.98±0.09, Figure 6b).”

Acute Aβ injection into p301L mice induced p-tau pathology in neurons surrounding the injection site in the LGN and hippocampus, compared to the contralateral side.

“Surrounding the injection site, p-tau bearing neurons were evident. These increases were immediately apparent by comparisons to the contralateral Hippocampus/LGN (Figure 9b).”

EpoD co-treatment with Aβ normalized SMI31 labeling asymmetry in the optic tract and optic nerve in Aβ-injected mice.

“we found EpoD dosing normalized SMI31 labeling asymmetry in the OT (Figure 6a) and the ON (Figure 6b) in the Aβ-injected mice.”

Aβ injection into the left LGN of p301L tau mice resulted in significant reduction in retinal ganglion cell (RGC) density asymmetry in the retina at 8 weeks compared to vehicle controls (0.83±0.098 vs 1.04±0.075).

“Comparison of density asymmetry between groups revealed a significant (p<0.01) reduction in cell bodies in the Aβ injected group (asymmetry = 0.83±0.098), compared to vehicle controls (1.04±0.075).”

EpoD co-treatment with Aβ prevented Aβ-induced RGC density asymmetry in the retina.

“EpoD-treated mice showed no significant RGC density asymmetry in the retina affected by Aβ (Figure 6c).”

In 3-month p301L mice, acute Aβ injection induced extensive p-tau pathology in the hippocampus and LGN exclusively on the injected side.

“we found no existing p-tau pathology in ON axons from either cohort, but did find extensive p-tau pathology in Aβ-treated mice in both the hippocampus and LGN (Figure 9c) exclusively on the injected side.”

Aβ injection into the left LGN of 10-month-old p301L tau mice resulted in a significant reduction in axial diffusion (AxD) asymmetry in the optic tract at 4 weeks compared to vehicle controls (0.92±0.059 vs 1.06±0.089).

“significant 13.2% reduction in axial diffusion, AxD vs. vehicle controls”

• Also stated in: § DTI and OCT alterations to the visual pathway after Aβ injection · plain

  “Aβ-treated mice showed significant reductions in AxD asymmetry (0.92±0.059) vs. vehicle controls (1.06±0.089)”

EpoD co-treatment with Aβ preserved Synapsin-1 labeling in the LGN that was lost in Aβ-injected cohorts.

“In the LGN, EpoD dosing appeared to preserve Syn-1 labeling that was lost in Aβ-injected cohorts (Figure 5).”

Optic nerve FA, AxD, and RAD asymmetry measures correlate with axon counts (FA r=0.76, p=0.001; AxD r=0.54, p=0.038; RAD r=-0.671, p=0.0062).

“significant correlations between ON FA (r = 0.76, p = 0.001), AxD (r = 0.54, p = 0.038) and RAD (r = −0.671, p = 0.0062) asymmetry measures and axon counts (Figure 7).”

Aβ injections in p301L mice precipitate measurable axon loss.

“We demonstrate that Aβ injections in p301L mice precipitate changes in DTI metrics as well as measureable axon loss.”

Longitudinal data suggest that alterations within the visual pathway manifest first in the LGN and OT and later in the ON.

“Longitudinal data suggest that alterations within the visual pathway manifest first in the LGN, OT and later in the ON, suggestive of a retrograde degeneration process.”

EpoD can preempt downstream neurodegeneration.

“our data suggest that the microtubule-stabilizing compound EpoD can prevent Aβ-induced tau phosphorylation and preempt downstream neurodegeneration.”

LGN Aβ injections lead to selective loss of white matter integrity by DTI in the mouse visual system.

“Our data reveal that LGN Aβ injections lead to selective loss of WM integrity by DTI, which appears to correlate with axon loss.”

EpoD can prevent Aβ-induced tau phosphorylation.

“our data suggest that the microtubule-stabilizing compound EpoD can prevent Aβ-induced tau phosphorylation and preempt downstream neurodegeneration.”

Aβ injections in p301L mice precipitate changes in DTI metrics.

“We demonstrate that Aβ injections in p301L mice precipitate changes in DTI metrics as well as measureable axon loss.”

The loss of white matter integrity by DTI appears to correlate with axon loss.

“Our data reveal that LGN Aβ injections lead to selective loss of WM integrity by DTI, which appears to correlate with axon loss.”

In this study, AxD measures were reduced relative to controls.

“In AD, AxD measures increase relative to controls, while we found reductions in measures of AxD 42.”

In this study, EpoD-treated mice showed much lower levels of tau pathology after two months of dosing.

“Our data recapitulate these findings, showing much lower levels of tau pathology among EpoD treated mice after two months of dosing.”

Aβ injection is able to induce local tauopathy even in mice without abundant pre-existing tau aggregates.

“As shown in Figure 9, Aβ injection is able to induce local tauopathy even in mice without abundant pre-existing tau aggregates.”

This axonal damage can be detected by DTI.

“This axonal damage can be detected by DTI, and the findings mirror several aspects of clinical data obtained from patients with AD.”

A 'dying-back' pattern was observed emanating from the location of the Aβ injection, in which axons die-back from the synapse.

“We observed a ‘dying-back’ pattern emanating from the location of the Aβ injection, in which axons die-back from the synapse, leading to neuronal loss.”

EpoD dosing prevents acute, local tau phosphorylation induced by Aβ that precedes later synapse, axon and cell loss.

“Furthermore, our data suggest that EpoD dosing prevents acute, local tau phosphorylation induced by Aβ that precedes later synapse, axon and cell loss.”

Epothilone D administration limits the induction of p-tau pathology.

“Epothilone D administration is sufficient to prevent this damage, limiting the induction of p-tau pathology and preventing downstream degeneration in the OT, ON and RGCs.”

Epothilone D administration prevents downstream degeneration in the OT, ON and RGCs.

“Epothilone D administration is sufficient to prevent this damage, limiting the induction of p-tau pathology and preventing downstream degeneration in the OT, ON and RGCs.”

Epothilone D administration is sufficient to prevent this damage.

“Epothilone D administration is sufficient to prevent this damage, limiting the induction of p-tau pathology and preventing downstream degeneration in the OT, ON and RGCs.”

This study demonstrates the importance of tau pathology induction to changes in white matter connectivity.

“the importance of tau pathology induction to changes in white matter connectivity”

Extracellular Aβ can stimulate tau phosphorylation and aggregation in neurons with axons projecting into the injection site in p301L mice, but not wild type mice.

“extracellular accumulations of Aβ can stimulate tau phosphorylation and aggregation in neurons with axons projecting into the injection site in mice expressing the mutant FTDP-17 (p301L) form of human tau, but not wild type mice19,20,22.”

• cites [19] Ghoshal, 2002, Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer's disease, Exp. Neurol. sourceNot checked — no full text of the source
• cites [20] Gotz, 2001, Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils, Science sourceNot checked — no full text of the source
• cites [22] Grandjean, 2016, Complex interplay between brain function and structure during cerebral amyloidosis in APP transgenic mouse strains revealed by multi-parametric MRI comparison, Neuroimage sourceNot checked — no full text of the source

Aβ-induced tau pathology may spread through axons in a retrograde manner.

“Aβ-induced tau pathology may spread through axons in a retrograde manner17,21,22.”

• cites [17] Drager, 1980, Origins of crossed and uncrossed retinal projections in pigmented and albino mice, J. Comp. Neurol. sourceNot checked — no full text of the source
• cites [21] Gouw, 2008, Heterogeneity of white matter hyperintensities in Alzheimer's disease: post-mortem quantitative MRI and neuropathology, Brain sourceNot checked — no full text of the source
• cites [22] Grandjean, 2016, Complex interplay between brain function and structure during cerebral amyloidosis in APP transgenic mouse strains revealed by multi-parametric MRI comparison, Neuroimage sourceNot checked — no full text of the source

This study demonstrates white matter disruption resulting from localized Aβ.

“This study demonstrates white matter disruption resulting from localized Aβ”

EpoD may mediate its protective effect by blocking localized, acute Aβ-induced tau phosphorylation.

“our data suggest that EpoD may mediate its protective effect by blocking localized, acute Aβ-induced tau phosphorylation.”

After Aβ injection into the LGN, DTI changes appeared first in the LGN and optic tract, then subsequently in the optic nerve.

“Changes appeared first in the LGN and OT, then subsequently in the ON.”

The temporospatial pattern of alterations in the visual pathway is suggestive of a retrograde degeneration process.

“Longitudinal data suggest that alterations within the visual pathway manifest first in the LGN, OT and later in the ON, suggestive of a retrograde degeneration process.”

Axonal degeneration may propagate from the injection site toward cell bodies.

“Collectively, our work demonstrates the critical role of pathological tau to enable Aβ-induced axonal damage and the temporospatial profile of axonal degeneration, which may propagate from the injection site toward cell bodies.”

Pathological tau is critical to enable Aβ-induced axonal damage.

“Collectively, our work demonstrates the critical role of pathological tau to enable Aβ-induced axonal damage and the temporospatial profile of axonal degeneration, which may propagate from the injection site toward cell bodies.”

In a previous study, prophylactic dosing with EpoD was sufficient to ameliorate axonal dystrophy.

“In a previous study, prophylactic dosing with EpoD was sufficient to ameliorate axonal dystrophy30.”

• cites [30] Kastyak-Ibrahim, 2013, Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice, Magn. Reson. Imaging sourceNot checked — no full text of the source

Previous pharmacokinetic modeling experiments suggest that EpoD has a residence time in the brain >10 days after a single dose at 3 mg/kg.

“Previous pharmacokinetic modeling experiments suggest that EpoD has a residence time in the brain >10 days after a single dose at 3mg/kg 30.”

• cites [30] Kastyak-Ibrahim, 2013, Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice, Magn. Reson. Imaging sourceNot checked — no full text of the source

The in vivo imaging approach paired with histology enabled detection of the temporospatial profile of degeneration.

“Our in vivo imaging approach paired with histology enabled us to detect the temporospatial profile of degeneration.”

Microtubule stabilizers such as EpoD may have a therapeutic effect sufficient to reduce tau pathology as well as synapse, axon and cell losses induced by Aβ.

“Our data suggest that microtubule stabilizers such as EpoD may have a therapeutic effect sufficient to reduce tau pathology as well as synapse, axon and cell losses induced by Aβ.”

Aβ injection can induce retrograde axonal damage in p301L mice.

“In summary, our data demonstrates that Aβ injection can induce retrograde axonal damage in p301L mice.”

The dying-back pattern leads to neuronal loss.

“We observed a ‘dying-back’ pattern emanating from the location of the Aβ injection, in which axons die-back from the synapse, leading to neuronal loss.”

Axonal damage and dysfunction may be a key initial step in tau-mediated neurodegeneration.

“These findings suggest that axonal damage and dysfunction may be a key initial step in tau-mediated neurodegeneration.”

The findings mirror several aspects of clinical data obtained from patients with AD.

“This axonal damage can be detected by DTI, and the findings mirror several aspects of clinical data obtained from patients with AD.”

The AxD measurement in the OT may follow the pattern of transient reduction followed by increase.

“Our measurement of AxD may follow this pattern in the OT, which shows early (4 week) reduction, then later normalization by 8 weeks.”

The difference in AxD changes between this study and human AD may be explained by microenvironment differences after acute vs. chronic axonal degeneration.

“This difference may be explained by microenvironment differences after acute vs. chronic axonal degeneration.”