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In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies.

ABSTRACT: Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborization are characteristic and can be quantified in vivo, with [¹¹C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive supranuclear palsy - Richardson's Syndrome (PSP-RS; n = 22) and amyloid-negative (determined by [¹¹C]PiB PET) Corticobasal Syndrome (Cortiobasal degeneration, CBD; n =14), as neurodegenerative disease models, in this proof-of-concept study. Compared to controls (n = 27), PSP-RS and CBD patients had widespread reductions in cortical ODI, and [¹¹C]UCB-J non-displaceable binding potential (BP_ND) in excess of atrophy. In PSP-RS and CBD separately, regional cortical ODI was significantly associated with [¹¹C]UCB-J BP_ND in disease-associated regions (p < 0.05, FDR corrected). Our findings indicate that reductions in synaptic density and dendritic complexity in PSP-RS and CBD are more severe and extensive than atrophy. Furthermore, both measures are tightly coupled in vivo, furthering our understanding of the pathophysiology of neurodegeneration, and applicable to studies of early neurodegeneration with a safe and widely available MRI platform.

SUBMITTER: Mak E

PROVIDER: S-EPMC8209289 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nucleoporin 98 is a nuclear pore complex component that is mislocalized in Alzheimer's disease and the alteration in nucleoporin 98 has been attributed to tau. In order to determine if nucleoporin 98 mislocalization is a general feature of tauopathies, we assessed the localization of nucleoporin 98 in neurons in primary tauopathies, including frontotemporal lobar degeneration-tau, corticobasal degeneration and progressive supranuclear palsy. Immunofluorescence staining was performed on frontal cortex and occipital cortex tissue from cases of primary tauopathies and controls without neurodegenerative disease using antibodies to identify nucleoporin 98, phospho-tau (Ser202, Thr205) monoclonal antibody and neuronal marker microtubule-associated protein 2. The stained tissue was imaged by fluorescence microscopy and the number of neurons with mislocalized nucleoporin 98 and phospho-tau (Ser202, Thr205) monoclonal antibody staining was quantified. In frontal cortex tissue, all primary tauopathies examined demonstrated significantly increased numbers of neurons with abnormal localization of nucleoporin 98 along the nuclear envelope compared with control tissue. Additionally, frontotemporal lobar degeneration-tau and corticobasal degeneration in the frontal cortex demonstrated significantly increased numbers of neurons with a cytoplasmic mislocalization of nucleoporin 98 compared with control tissue. The number of neurons with mislocalized nucleoporin 98 was significantly correlated with the number of neurons with phospho-tau (Ser202, Thr205) monoclonal antibody-positive tau staining. In the occipital cortex, which is relatively spared from pathological tau accumulations in these primary tauopathies, the localization of nucleoporin 98 was not significantly altered. This study demonstrates that nucleoporin 98 mislocalization is a feature of primary tauopathies and is associated with pathological tau accumulation. In the context of prior research demonstrating nucleoporin 98 mislocalization in Alzheimer's disease and an interaction between tau and nucleoporin 98, these results further support the hypothesis that pathological tau may contribute to nucleoporin 98 mislocalization. Given the critical role of the nuclear pore complex in nucleocytoplasmic transport, the identification of nucleoporin 98 mislocalization in primary tauopathies highlights a potential pathophysiological disruption in these disorders.

Project description:BackgroundSynaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits.ObjectiveIn this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression.MethodsOur cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity.ResultsWe found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003).ConclusionsWe provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies.

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