Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) have ...in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations. They also occur in non-diseased individuals and can co-exist in the same brain without or with a clinical picture of a distinct dementing or movement disorder. In this review, we discuss the co-existence of these pathologies and potential additive effects in the human brain as well as related functional findings on cross-seeding and molecular interactions between these aggregates/proteins. We conclude that there is evidence for interactions at the molecular level as well as for additive effects on brain damage by multiple pathologies occurring in different functionally important neurons. Based upon this information, we hypothesize a cascade of events that may explain general mechanisms in the development of neurodegenerative disorders: (1) distinct lesions are a prerequisite for the development of a distinct disease (e.g., primary age-related tauopathy for AD), (2) disease-specific pathogenic events further trigger the development of a specific disease (e.g., Aβ aggregation in AD that exaggerate further Aβ and AD-related τ pathology), (3) the symptomatic disease manifests, and (4) neurodegenerative co-pathologies may be either purely coincidental or (more likely) have influence on the disease development and/or its clinical presentation.
Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have ...developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
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•A postmortem bedside surgical procedure was developed for COVID-19 and control patients•Ciliated cells are the main target cell type for SARS-CoV-2 in the respiratory mucosa•Sustentacular cells (non-neuronal) are the main target cell type in the olfactory mucosa•No evidence for infection of olfactory sensory neurons or olfactory bulb parenchyma
Postmortem samples of respiratory and olfactory mucosa and whole olfactory bulbs are harvested immediately after the death of COVID-19 patients revealing ciliated cells and sustentacular cells but not olfactory sensory neurons as the main target cell types for SARS-CoV-2 infection and replication.
Primary pathologies including amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) develop many years before the onset of dementia symptoms in Alzheimer's disease (AD). Age-related small vessel ...disease (SVD) is common in elderly subjects and may contribute to the clinical syndrome of AD. Each type of pathology shows a specific spatio-temporal sequence of spreading in the brain. Here, we review neuropathological and neuroimaging findings (PET tracers of Aβ and NFT, MRI markers of SVD) to assess whether staging of these primary pathologies is useful to predict clinical symptoms in AD. On the basis of neuropathological data, early stages of Aβ plaque and NFT pathology distribution occur in preclinical AD, but advanced stages with spreading into further brain regions are associated with dementia symptoms. Amyloid PET presumably detects Aβ in advanced neuropathological Aβ stages, and increased global amyloid PET uptake is associated with clinical worsening in non-demented subjects. Tau PET may provide additional predictive value by detecting NFT in the allocortex. There is weak evidence that SVD is related to amyloid or NFT pathology. Global volume of MRI-assessed white matter hyperintensities (WMH) contribute in addition to biomarker levels of Aβ to predict cognitive decline. Regional differences of the effect of WMH on cognition have been demonstrated but are not yet established as a biomarker in AD. In conclusion, biomarkers for amyloid and tau pathology allow a distinction between early and advanced stages of AD, but a subgroup of pathologically identified preclinical AD cases is not identified by the currently available biomarkers.
We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). ...Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.
Abstract A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) ...and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.
SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and ...screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α
-antitrypsin (α
AT), a highly abundant circulating serine protease inhibitor. Here, we report that α
AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α
AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α
AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α
AT-containing drugs has prospects for the therapy of COVID-19.
Objective:
Neuromyelitis optica (NMO) and multiple sclerosis (MS) are considered inflammatory demyelinating diseases with distinguishing pathological characteristics. NMO pathology shows perivascular ...immunoglobulin G and complement deposition, as well as an astrocytopathy with aquaporin‐4 (AQP4) loss. MS lesions reveal a profound, interindividual heterogeneity in immunopathological patterns of active demyelination, which has been challenged by the description of stage‐dependent sequences of pathological features. The aim of our study was to compare the histological characteristics of early active demyelinating NMO and MS brain lesions.
Methods:
Thirteen cases with supraspinal active demyelinating NMO lesions were analyzed using immunohistochemistry. Results were compared with the published characteristics of MS lesions.
Results:
A subset of supraspinal lesions from AQP4‐IgG‐seropositive NMO patients revealed both (1) complement activation products within macrophages at sites of active demyelination and (2) oligodendrocyte apoptosis and a preferential loss of myelin‐associated glycoprotein. These characteristics resemble features previously associated with MS lesion patterns II and III, and were present in addition to characteristic histopathological NMO features, namely loss of AQP4 and astrocytes.
Interpretation:
Early active demyelinating NMO lesions may show complement within macrophages and oligodendrocyte apoptosis associated with a selective loss of minor myelin proteins, in addition to typical NMO features. We hypothesize these findings occur simultaneously only in a subset of active demyelinating NMO lesions. These observations plausibly explain the findings of Barnett and Prineas and further support the concept of interindividual heterogeneity in MS. ANN NEUROL 2012;72:385–394.
The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been ...discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer's disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43
, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43
) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as AD
because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43
, pTDP-43
). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as AD
. Ten AD cases did not contain any TDP-43 pathology and were referred to as AD
. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of AD
cases, 63,6% of AD
and 100% of the AD
cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of AD
, in 16,6% of the AD
, and in none of the AD
cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from AD
to AD
and AD
with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in AD
cases.
Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we ...have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using tau as a model system we demonstrate that proteins with local sequence homology to tau amyloid nucleating regions can modify fibril nucleation, morphology, assembly and spreading of aggregates in cultured cells. Depending on the type of mutation such interactions inhibit or promote aggregation in a manner that can be predicted from structure. We find that these heterotypic amyloid interactions can result in the subcellular mis-localisation of these proteins. Moreover, equilibrium studies indicate that the critical concentration of aggregation is altered by heterotypic interactions. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and we discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.
Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct ...pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.
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