Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy
ConclusionsWe have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observatio ns. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an e...
Source: Translational Neurodegeneration - February 7, 2022 Category: Neurology Source Type: research
Mechanisms of motor symptom improvement by long-term Tai Chi training in Parkinson ’s disease patients
ConclusionsLong-term Tai Chi training improves motor function, especially gait and balance, in PD. The underlying mechanisms may include enhanced brain network function, reduced inflammation, improved amino acid metabolism, energy metabolism and neurotransmitter metabolism, and decreased vulnerability to dopaminergic degeneration.Trial registration This study has been registered at Chinese Clinical Trial Registry (Registration number: ChiCTR2000036036; Registration date: August 22, 2020). (Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - February 7, 2022 Category: Neurology Source Type: research
LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease
AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson ’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagyvia activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and ...
Source: Translational Neurodegeneration - January 31, 2022 Category: Neurology Source Type: research
Brain-derived neurotrophic factor in Alzheimer ’s disease and its pharmaceutical potential
AbstractSynaptic abnormalities are a cardinal feature of Alzheimer ’s disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitiv e impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker an...
Source: Translational Neurodegeneration - January 28, 2022 Category: Neurology Source Type: research
Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration
AbstractGlutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by...
Source: Translational Neurodegeneration - January 25, 2022 Category: Neurology Source Type: research
Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer ’s disease
ConclusionsCollectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging. (Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - January 6, 2022 Category: Neurology Source Type: research
Translational Neurodegeneration in the era of fast growing international brain research
(Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - January 2, 2022 Category: Neurology Source Type: research
Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia
ConclusionspGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD. (Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - December 10, 2021 Category: Neurology Source Type: research
Gram-negative bacteria and their lipopolysaccharides in Alzheimer ’s disease: pathologic roles and therapeutic implications
AbstractAlzheimer ’s disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the dev elopment of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS ha ve been sh...
Source: Translational Neurodegeneration - December 7, 2021 Category: Neurology Source Type: research
Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice
ConclusionThese results suggest that the transcranial ultrasound-based gamma-band entrainment technique can be an effective therapy for AD by reducing the A β load and improving brain connectivity. (Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - December 7, 2021 Category: Neurology Source Type: research
TLR2 and TLR4 in Parkinson ’s disease pathogenesis: the environment takes a toll on the gut
AbstractParkinson ’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, espe cially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic centra l nervous ...
Source: Translational Neurodegeneration - November 17, 2021 Category: Neurology Source Type: research
New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis
AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features a...
Source: Translational Neurodegeneration - November 15, 2021 Category: Neurology Source Type: research
The role of pathological tau in synaptic dysfunction in Alzheimer ’s diseases
AbstractAlzheimer ’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cogn itive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in sever al ways, i...
Source: Translational Neurodegeneration - November 10, 2021 Category: Neurology Source Type: research
Extensive frontal focused ultrasound mediated blood –brain barrier opening for the treatment of Alzheimer’s disease: a proof-of-concept study
ConclusionsThe repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. In addition, the BBB opening is potentially beneficial for amyloid removal in AD patients. (Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - November 5, 2021 Category: Neurology Source Type: research
Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson ’s disease: removing axonal debris
ConclusionsThe present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD. (Source: Translational Neurodegeneration)
Source: Translational Neurodegeneration - November 2, 2021 Category: Neurology Source Type: research
