Early Hippocampal Synaptic Loss Precedes Neuronal Loss and Associates with Early Behavioural Deficits in Three Distinct Strains of Prion Disease

Hilton, Kenneth; Cunningham, Colm; Reynolds, Richard A. K.; Perry, V. Hugh

doi:10.1371/journal.pone.0068062

Cited by 46 publications

(43 citation statements)

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“…Nevertheless, the precise role of glia in chronic neurodegeneration associated with prion disease has been under extensive debate and remains controversial [39, 57, 65, 66]. Microglia activation was shown to occur at much earlier stages than synaptic loss [24, 34, 35, 37, 67], which is considered to be an early neuron-specific pathological sign [68, 69]. Solid evidence in support of both neuroprotective phenotypes and inflammatory or neurotoxic phenotypes have been presented over the years [58, 61, 63, 67, 70–78].…”

Section: Discussionmentioning

confidence: 99%

Loss of region-specific glial homeostatic signature in prion diseases

Makarava

Chang

Molesworth

et al. 2019

Preprint

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13Background Chronic neuroinflammation is recognized as a major neuropathological hallmark in 14 a broad spectrum of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal 15 Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and 16 astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic 17 neurodegeneration, transform into reactive phenotypes in a region-and disease-specific manner. 18 Little is known about region-specific identity of glia in prion diseases. The current study was 19 designed to determine whether the region-specific homeostatic signature of glia changes with the 20 progression of prion diseases, and whether these changes occur in a region-dependent or universal 21 manner. Also of interest was whether different prion strains give rise to different reactive 22 phenotypes.23 Methods To answer these questions, we analyzed gene expression in thalamus, cortex, 24 hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using Nanostring 25 Neuroinflammation panel at subclinical, early clinical and advanced stages of the disease. 26 ResultsWe found that at the preclinical stage of the disease, region-specific homeostatic identities 27 were preserved. However, with the appearance of clinical signs, region-specific signatures were 28 partially lost and replaced with a neuroinflammation signature. While the same sets of genes were 29 activated by both prion strains, the timing of neuroinflammation and the degree of activation in 30 different brain regions was strain-specific. Changes in astrocyte function scored at the top of 31 activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway 32 responded to prion infection prior to activated microglia or neuron and neurotransmission 33 pathways. 34Conclusions The current work established neuroinflammation gene expression signature 35 associated with prion diseases. Our results illustrate that with the disease progression, the region-36 specific homeostatic transcriptome signatures are replaced by region-independent 37 neuroinflammation signature, which was common for prion strains with different cell tropism. The 38 prion-associated neuroinflammation signature identified in the current study overlapped only 39 partially with the microglia degenerative phenotype and the disease-associated microglia 40 phenotype reported for animal models of other neurodegenerative diseases. 41 3 Background 45 Chronic neuroinflammation is recognized as one of the major neuropathological hallmarks 46 of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia, 47 Amyotrophic Lateral Sclerosis, and prion diseases [1]. Chronic neuroinflammation manifests itself 48 as a sustained activation of glial cells and the transformation of their homeostatic phenotype into 49 reactive phenotypes [2, 3]. Transcriptome analysis and single-cell RNA-sequencing revealed 50 considerable region-specific homeosta...

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Section: Discussionmentioning

confidence: 99%

Loss of region-specific glial homeostatic signature in prion diseases

Makarava

Chang

Molesworth

et al. 2019

Preprint

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“…The ME7 model of prion disease offers a tractable model to study neuroanatomical spread of neuronal pathology. We have identified very significant thalamic pathology in mice inoculated with ME7, 79A or 22L with robust neuronal loss in the posterior areas of the thalamus at later stages of disease in ME7, 79A and 22L strains [13] and PrP Sc deposition, astrocytosis and microgliosis occurring at early stages (12 weeks) [14]. There is evidence for pathology in the thalamus in prion disease in other experimental animals [15–17] and in the multiple forms of human prion disease including new variant and sporadic Creutzfeldt–Jakob diseases (sCJD) [18,19], fatal familial insomnia (FFI) [20,21] and Gerstmann‐Straussler‐Scheinker (GSS) disease [22].…”

Section: Introductionmentioning

confidence: 88%

“…We have previously examined neuropathology in multiple brain regions, in multiple strains at key time points in the progression of prion disease [8,13,14]. Here, our aim is to characterize thalamic pathology in ME7 mice when significant neurodegeneration has occurred in this structure, which coincides with failure on motor coordination and muscle strength tasks, demonstrating that these mice are beginning the terminal stages of disease (18 weeks post‐inoculation).…”

Section: Introductionmentioning

confidence: 99%

At the centre of neuronal, synaptic and axonal pathology in murine prion disease: degeneration of neuroanatomically linked thalamic and brainstem nuclei

Reis

Hennessy

Murray

et al. 2015

Neuropathology Appl Neurobio

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AimsThe processes by which neurons degenerate in chronic neurodegenerative diseases remain unclear. Synaptic loss and axonal pathology frequently precede neuronal loss and protein aggregation demonstrably spreads along neuroanatomical pathways in many neurodegenerative diseases. The spread of neuronal pathology is less studied.MethodsWe previously demonstrated severe neurodegeneration in the posterior thalamus of multiple prion disease strains. Here we used the ME7 model of prion disease to examine the nature of this degeneration in the posterior thalamus and the major brainstem projections into this region.ResultsWe objectively quantified neurological decline between 16 and 18 weeks post‐inoculation and observed thalamic subregion‐selective neuronal, synaptic and axonal pathology while demonstrating relatively uniform protease‐resistant prion protein (PrP) aggregation and microgliosis across the posterior thalamus. Novel amyloid precursor protein (APP) pathology was particularly prominent in the thalamic posterior (PO) and ventroposterior lateral (VPL) nuclei. The brainstem nuclei forming the major projections to these thalamic nuclei were examined. Massive neuronal loss in the PO was not matched by significant neuronal loss in the interpolaris (Sp5I), while massive synaptic loss in the ventral posteromedial nucleus (VPM) did correspond with significant neuronal loss in the principal trigeminal nucleus. Likewise, significant VPL synaptic loss was matched by significant neuronal loss in the gracile and cuneate nuclei.ConclusionThese findings demonstrate significant spread of neuronal pathology from the thalamus to the brainstem in prion disease. The divergent neuropathological features in adjacent neuronal populations demonstrates that there are discrete pathways to neurodegeneration in different neuronal populations.

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“…Artificial inhibition of mitochondrial respiratory chain function in vivo and in vitro revealed the importance of ATP levels in controlling synaptic energetic state and in maintaining synaptic integrity and functionality [17,18]. Recent work has recognized synaptic dysfunction and degeneration in response to mitochondrial dysfunction as an early feature in neurodegenerative disease [19,20].…”

Section: Introductionmentioning

confidence: 99%

Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease

Chrysostomou

Grady

Laude

et al. 2015

Neuropathology Appl Neurobio

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AimsCerebellar ataxia is common in patients with mitochondrial disease, and despite previous neuropathological investigations demonstrating vulnerability of the olivocerebellar pathway in patients with mitochondrial disease, the exact neurodegenerative mechanisms are still not clear. We use quantitative quadruple immunofluorescence to enable precise quantification of mitochondrial respiratory chain protein expression in Purkinje cell bodies and their synaptic terminals in the dentate nucleus.MethodsWe investigated NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 protein expression in 12 clinically and genetically defined patients with mitochondrial disease and ataxia and 10 age‐matched controls. Molecular genetic analysis was performed to determine heteroplasmy levels of mutated mitochondrial DNA in Purkinje cell bodies and inhibitory synapses.ResultsOur data reveal that complex I deficiency is present in both Purkinje cell bodies and their inhibitory synapses which surround dentate nucleus neurons. Inhibitory synapses are fewer and enlarged in patients which could represent a compensatory mechanism. Mitochondrial DNA heteroplasmy demonstrated similarly high levels of mutated mitochondrial DNA in cell bodies and synapses.ConclusionsThis is the first study to use a validated quantitative immunofluorescence technique to determine complex I expression in neurons and presynaptic terminals, evaluating the distribution of respiratory chain deficiencies and assessing the degree of morphological abnormalities affecting synapses. Respiratory chain deficiencies detected in Purkinje cell bodies and their synapses and structural synaptic changes are likely to contribute to altered cerebellar circuitry and progression of ataxia.

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Early Hippocampal Synaptic Loss Precedes Neuronal Loss and Associates with Early Behavioural Deficits in Three Distinct Strains of Prion Disease

Cited by 46 publications

References 46 publications

Loss of region-specific glial homeostatic signature in prion diseases

Loss of region-specific glial homeostatic signature in prion diseases

At the centre of neuronal, synaptic and axonal pathology in murine prion disease: degeneration of neuroanatomically linked thalamic and brainstem nuclei

Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease

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