In this review, the amyloid cascade is summarized along with the results of major clinical trials that have sought to target the amyloid cascade for therapeutic intervention. The distinction between theory, largely unaltered, and proof of concept that might temper the theory, is highlighted.
The growing burden of neurodegenerative diseases on patients, their families, and health care providers has also stimulated some exciting new developments in the field. This issue of Laboratory Investigation provides a broad view of the field of neurodegenerative diseases with diverse papers focusing on basic research, clinicopathological correlation, neuropathological diagnosis.
The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases
Increasing lines of evidence have shown beneficial effects of physical exercise against or delay neurodegeneration. However, the mechanisms of their beneficial effects are confusing because it involves the connection between the brain and muscles. This review summarizes these findings and discusses the differential and common effects of aerobic versus resistance exercises.
This review discusses the templated spread of α-synuclein (α-syn) pathology in neurodegenerative disease from the perspective of proteopathic α-syn seeds. Recent discoveries concerning the structure and cell biology of pathological α-syn aggregates are highlighted.
Neurodegenerative diseases evolve in multi-factorial manners, yet coherent paradigms are emerging. Both Tau and TDP-43 proteinopathies are linked to multiple upstream influences, and both are connected with numerous deleterious downstream endpoints. Gene variants can be either disease-specific, or, exert influence on the misfolding pathology itself rather than the upstream cause.
Brain inclusions of the microtubule-associated protein tau are prominent pathological features in a spectrum of neurodegenerative diseases. MAPT gene mutations that encodes tau can directly cause neurodegeneration. Herein, the authors review what is known about MAPT mutations dysfunctions with a focus on the prion-like properties of tau protein.
Dissecting α-synuclein inclusion pathology diversity in multiple system atrophy: implications for the prion-like transmission hypothesis
Leveraging an extensive panel of α-synuclein antibodies that targets a wide range of epitopes, the authors provide evidence that multiple system atrophy α-synuclein inclusions display distinct misfolded strain-like characteristics divergent from Lewy body diseases. The findings also indicate that in multiple system atrophy α-synuclein prion-like strains are likely inherently mutable.
Clinical diagnoses among individuals with primary age-related tauopathy versus Alzheimer’s neuropathology
The authors identified and compared the primary and contributing diagnoses for people with primary age-related tauopathy (PART) to those with Alzheimer’s disease neuropathologic change (ADNP). Clinicians diagnose AD less frequently in those with PART, recognizing a distinction in the clinical presentation between PART and ADNP.
In this study, the authors show that RIP1/RIP3/MLKL-mediated necroptosis is activated in a mouse model of Parkinson’s disease. Blockade of necroptosis through pharmacological intervention by Nec-1 or deletion of RIP3/MLKL gene increased dopamine levels and the number of dopaminergic neurons in mice. Moreover, necroptosis enhanced the expression of pro-inflammatory genes, which may have initiated neuroinflammation and in turn aggravated dopaminergic neuron necroptosis.
The authors developed nervous-system-specific Nrbf2 knockout mice and found that they exhibited profound learning and memory deficits. RNAseq analyses have identified altered expression of genes related to protein folding and quality control. Aberrant aggregates of some of these key proteins are evident in the hippocampus.
The authors report that pathogenic TDP-43 is increased and closely associated with mitochondria in degenerating skeletal muscles of patients with inclusion body myositis, while key subunits of mitochondrial oxidative phosphorylation complexes I and III are reduced, implying a potential role of mitochondria and associated TDP-43 for disease pathogenesis.
N-terminal sequences in matrin 3 mediate phase separation into droplet-like structures that recruit TDP43 variants lacking RNA binding elements
RNA binding proteins associated with amyotrophic lateral sclerosis and muscle myopathy possess sequence elements that bear resemblance to yeast prion domains. Fusion proteins of the nuclear matrix protein matrin 3 (MATR3), transactive response DNA binding proteinTARDBP43 (TDP43) or the RNA binding protein FUS with yellow fluorescent protein or mCherry were used to examine phase separation and protein interaction in mouse C2C12 myoblast cells. The authors show that N-terminal sequences in MATR3 can mediate phase separation into intranuclear droplet-like structures, which recruit TDP43 variants lacking RNA binding elements.
In this paper the authors outline the known neuropathology of mild traumatic brain injury (mTBI). They employed immunohistochemistry and gene expression profiling techniques in two post-mortem cases in order to propose markers of DNA damage as the driver of pathology and symptoms after mTBI.
In this study, the authors show that machine learning is a useful tool for complex pathological assessment of Alzheimer disease and other tauopathies. Using deep learning classifiers, we now have the potential to integrate cell- and region-specific annotations with clinical, genetic, and molecular data, providing unbiased data for clinicopathological correlations that will enhance our knowledge of the neurodegeneration.
Isocitrate dehydrogenase (IDH) mutations can be identified by gas chromatography mass spectrometry (GC/MS). The sensitivity and specificity are 100% in gliomas for the accumulation of 2-hydroxyglutarate (2-HG), whereas the ratio of 2-HG/glutamic acid also serves as a reliable index. The modified mini-column GC/MS method could shorten the procedure to 40 min for rapid diagnosis.
In a series of Huntington’s disease (HD) brains, the authors identified phospho-tau aggregation in all cases. In contrast to recent observations suggesting a new role for tau in HD pathogenesis, the tau pathology in our cases was classifiable into known diagnostic entities and most likely represents non-specific age- or perhaps trauma-related changes.
This study shows a negative regulation of autophagy-related RNA transcripts and the upregulation and downregulation of p62 and LC3-B proteins, respectively, in the central nervous system of scrapie-infected transgenic mice at clinical stage. These findings likely reflect an impairment of the autophagic pathway at the late symptomatic stage of prion infection.
Role of prion protein glycosylation in replication of human prions by protein misfolding cyclic amplification
Protein misfolding cyclic amplification (PMCA) is a technique able to detect minute amount of disease-related prion protein (PrPD), but limited results have been obtained with human prions with the exception of variant Creutzfeldt-Jakob disease (variant CJD). The study demonstrates that the use of substrates with deglycosylated PrP strongly increases PrPD amplification efficiency by PMCA for all tested CJD subtypes. The enhanced PMCA efficiency may allow for the developing of a sensitive, non-invasive, diagnostic tests for the different CJD subtypes based on body fluids or easily accessible peripheral tissues.