Vulnerability In Neurodegenerative Diseases Research Articles

Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases.

The selective vulnerability of specific neuronal subtypes is a hallmark of neurodegenerative diseases. In this Review, I summarize our current understanding of the brain regions and cell types that are selectively vulnerable in different neurodegenerative diseases and describe the proposed underlying cell-autonomous and non-cell-autonomous mechanisms. I highlight how recent methodological innovations - including single-cell transcriptomics, CRISPR-based screens and human cell-based models of disease - are enabling new breakthroughs in our understanding of selective vulnerability. An understanding of the molecular mechanisms that determine selective vulnerability and resilience would shed light on the key processes that drive neurodegeneration and point to potential therapeutic strategies to protect vulnerable cell populations.

SBT-272 improves TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity, motility, and function

Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNs in vitro. In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the disease in vivo led to a significant reduction in astrogliosis, microgliosis, and TDP-43 pathology in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.

Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.

Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

Exploration of vulnerability in neurodegenerative diseases: Determination skills of genetic and environmental risk factors

Neurodegenerative diseases (ND) affect a large portion of our elder population with cognitive impairment, impaired movement due to loss of balance or muscle weakness in motor neuron. Due to their irreversible nature they present a significant public health burden through the demand on our health care system as well as by unmet therapeutic measures that influence socioeconomic decision processes, while our current population is transitioned to an aged community. Here we introduce top 3 of the most prevalent NDs and examine preventive alternatives along with the available research on both genetic and environmental risk factors. While many questions remain, genetic predisposition combined with environmental exposures may be to blame for a large number of these cases. Utilizing emerging multi-fold omics technologies, early prevention aided by development of biomarker can help to identify risk factors and to envision new avenue in new treatments option in the future.

Exploration of vulnerability in neurodegenerative diseases: Determination skills of genetic and environmental risk factors

Exploration of vulnerability in neurodegenerative diseases: Determination skills of genetic and environmental risk factors

Impaired Phasic Discharge of Locus Coeruleus Neurons Based on Persistent High Tonic Discharge-A New Hypothesis With Potential Implications for Neurodegenerative Diseases.

The locus coeruleus (LC) is a small brainstem nucleus with widely distributed noradrenergic projections to the whole brain, and loss of LC neurons is a prominent feature of age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This article discusses the hypothesis that in early stages of neurodegenerative diseases, the discharge mode of LC neurons could be changed to a persistent high tonic discharge, which in turn might impair phasic discharge. Since phasic discharge of LC neurons is required for the release of high amounts of norepinephrine (NE) in the brain to promote anti-inflammatory and neuroprotective effects, persistent high tonic discharge of LC neurons could be a key factor in the progression of neurodegenerative diseases. Transcutaneous vagal stimulation (t-VNS), a non-invasive technique that potentially increases phasic discharge of LC neurons, could therefore provide a non-pharmacological treatment approach in specific disease stages. This article focuses on LC vulnerability in neurodegenerative diseases, discusses the hypothesis that a persistent high tonic discharge of LC neurons might affect neurodegenerative processes, and finally reflects on t-VNS as a potentially useful clinical tool in specific stages of AD and PD.

Selective vulnerability in neurodegenerative diseases.

Neurodegenerative diseases have two general characteristics that are so fundamental we usually take them for granted. The first is that the pathology associated with the disease only affects particular neurons ('selective neuronal vulnerability'); the second is that the pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The mechanisms underpinning selective neuronal and regional vulnerability have been difficult to dissect, but the recent application of whole-genome technologies, the development of mouse models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable neurons are beginning to shed some light on these fundamental features of neurodegenerative diseases. Here we detail our emerging understanding of the underlying biology of selective neuronal vulnerability and outline some of the areas in which our understanding is incomplete.

Direct conversion of human pluripotent stem cells into cranial motor neurons using a piggyBac vector

Human pluripotent stem cells (PSCs) are widely used for in vitro disease modeling. One of the challenges in the field is represented by the ability of converting human PSCs into specific disease-relevant cell types. The nervous system is composed of a wide variety of neuronal types with selective vulnerability in neurodegenerative diseases. This is particularly relevant for motor neuron diseases, in which different motor neurons populations show a different susceptibility to degeneration. Here we developed a fast and efficient method to convert human induced Pluripotent Stem Cells into cranial motor neurons of the branchiomotor and visceral motor subtype. These populations represent the motor neuron subgroup that is primarily affected by a severe form of amyotrophic lateral sclerosis with bulbar onset and worst prognosis. This goal was achieved by stable integration of an inducible vector, based on the piggyBac transposon, allowing controlled activation of Ngn2, Isl1 and Phox2a (NIP). The NIP module effectively produced electrophysiologically active cranial motor neurons. Our method can be easily extended to PSCs carrying disease-associated mutations, thus providing a useful tool to shed light on the cellular and molecular bases of selective motor neuron vulnerability in pathological conditions.

Contribution of Neuroepigenetics to Huntington's Disease.

Unbalanced epigenetic regulation is thought to contribute to the progression of several neurodegenerative diseases, including Huntington’s disease (HD), a genetic disorder considered as a paradigm of epigenetic dysregulation. In this review, we attempt to address open questions regarding the role of epigenetic changes in HD, in the light of recent advances in neuroepigenetics. We particularly discuss studies using genome-wide scale approaches that provide insights into the relationship between epigenetic regulations, gene expression and neuronal activity in normal and diseased neurons, including HD neurons. We propose that cell-type specific techniques and 3D-based methods will advance knowledge of epigenome in the context of brain region vulnerability in neurodegenerative diseases. A better understanding of the mechanisms underlying epigenetic changes and of their consequences in neurodegenerative diseases is required to design therapeutic strategies more effective than current strategies based on histone deacetylase (HDAC) inhibitors. Researches in HD may play a driving role in this process.

Catastrophic cliffs: a partial suggestion for selective vulnerability in neurodegenerative diseases.

For each of the neurodegenerative syndromes, we now know many pathogenic and/or causative genetic risk loci. Here, I suggest that this wealth of knowledge now allows us to start to understand what are the specific vulnerabilities of different neuronal typesand to suggest that each neuronal typeis closer to different modes of catastrophic failure. I suggest that this is part of the basis for selective vulnerability in neurodegenerative disease.

Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve

BackgroundThe central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial.ObjectiveThis study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology.MethodsIn vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein.ResultsIn rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation.ConclusionActivity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases.

Primary progressive aphasia and the evolving neurology of the language network.

Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.

Are there susceptibility factors for primary progressive aphasia?

The determinants of selective vulnerability in neurodegenerative diseases remain elusive. The asymmetric loss of neurons in primary progressive aphasia offers a unique setting for addressing this question. Although no factor can yet account for the selective vulnerability of the left hemisphere language network to degenerative diseases, a few themes are emerging as potential targets of further investigation.

Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome

Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network "epicenters" whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures.

Selective vulnerability in Alzheimer's disease: Amyloid precursor protein and p75NTR interaction

Selective neuronal vulnerability in neurodegenerative diseases is poorly understood. In Alzheimer's disease, the basal forebrain cholinergic neurons are selectively vulnerable, putatively because of their expression of the cell death mediator p75(NTR) (the common neurotrophin receptor), and its interaction with proapoptotic ligands pro-nerve growth factor and amyloid-beta peptide. However, the relation between amyloid precursor protein (APP) and p75(NTR) has not been described previously. APP and p75(NTR) were assayed for interaction by coimmunoprecipitation in vitro and in vivo, yeast two-hybrid assay, bioluminescence resonance energy transfer, and confocal microscopy. Effects on APP processing and signaling were studied using immunoblotting, enzyme-linked immunosorbent assays, and luciferase reporter assays. The results of this study are as follows: (1) p75(NTR) and APP interact directly; (2) this interaction is modified by ligands nerve growth factor and beta-amyloid; (3) APP and p75(NTR) colocalization in vivo is modified in Alzheimer's model transgenic mice; (4) APP processing is altered by p75(NTR), and to a lesser extent, p75(NTR) processing is altered by the presence of APP; (5) APP-dependent transcription mediated by Fe65 is blocked by p75(NTR); and (6) coexpression of APP and p75(NTR) triggers cell death. These results provide new insight into the emerging signaling network that mediates the Alzheimer's phenotype and into the mechanism of basal forebrain cholinergic neuronal selective vulnerability. In addition, the results argue that the interaction between APP and p75(NTR) may represent a therapeutic target in Alzheimer's disease.

Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases

According to a long-standing hypothesis, aging is mainly caused by accumulation of nuclear (n) DNA damage in differentiated cells such as neurons due to insufficient nDNA repair during lifetime. In line with this hypothesis it was until recently widely accepted that neuron loss is a general consequence of normal aging, explaining some degree of decline in brain function during aging. However, with the advent of more accurate procedures for counting neurons, it is currently widely accepted that there is widespread preservation of neuron numbers in the aging brain, and the changes that do occur are relatively specific to certain brain regions and types of neurons. Whether accumulation of nDNA damage and decline in nDNA repair is a general phenomenon in the aging brain or also shows cell-type specificity is, however, not known. It has not been possible to address this issue with the biochemical and molecular-biological methods available to study nDNA damage and nDNA repair. Rather, it was the introduction of autoradiographic methods to study quantitatively the relative amounts of nDNA damage (measured as nDNA single-strand breaks) and nDNA repair (measured as unscheduled DNA synthesis) on tissue sections that made it possible to address this question in a cell-type-specific manner under physiological conditions. The results of these studies revealed a formerly unknown inverse relationship between age-related accumulation of nDNA damage and age-related impairment in nDNA repair on the one hand, and the age-related, selective, loss of neurons on the other hand. This inverse relation may not only reflect a fundamental process of aging in the central nervous system but also provide the molecular basis for a new approach to understand the selective neuronal vulnerability in neurodegenerative diseases, particularly Alzheimer's disease.

P3-350: Type 2 (Ca 2+ permeable) AMPA receptor: Its phenotype expression and roles in neuronal vulnerability in neurodegenerative diseases

P3-350: Type 2 (Ca 2+ permeable) AMPA receptor: Its phenotype expression and roles in neuronal vulnerability in neurodegenerative diseases

3‐Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the gene encoding Huntingtin. The mechanisms underlying the preferential degeneration of the striatum, the most striking neuropathological change in HD, are unknown. Of those probably involved, mitochondrial defects might play an important role. The behavioural and anatomical similarities found between HD and models using the mitochondrial toxin 3-nitropropionic acid (3NP) in rats and primates support this hypothesis. Here, we discuss the recently identified mechanisms of 3NP-induced striatal degeneration. Two types of important factor have been identified. The first are the 'executioner' components that have direct roles in cell death, such as c-Jun N-terminal kinase and Ca2+-activated protease calpains. The second are 'environmental' factors, such as glutamate, dopamine and adenosine, which modulate the striatal degeneration induced by 3NP. Interestingly, these recent studies support the hypothesis that 3NP and mutated Huntingtin have certain mechanisms of toxicity in common, suggesting that the use of 3NP might give new insights into the pathogenesis of HD. Research on 3NP provides additional proof that the neurochemical environment of a given neurone can determine its preferential vulnerability in neurodegenerative diseases.

Molecular approaches to cerebral laterality: Development and neurodegeneration

Little is understood about the genetic or epigenetic mechanisms that underlie brain asymmetry. Because higher cognitive functions such as language, constructional and spatial abilities, and attention are organized along the left/right axis, understanding the underpinnings of this process has significant implications for both developmental biology and cognitive neuroscience. However, scientists have begun to explore, in only the most preliminary manner, the influences of subtle biologically inherited brain asymmetries on human behavior and disease. Because brain asymmetry develops prenatally, the recognition of asymmetry in neurodegeneration implies a possible relationship between the development of cerebral laterality and regional vulnerability in neurodegenerative diseases. This suggests that the study of cerebral asymmetry and laterality is likely to be relevant to a number of degenerative conditions that were previously considered to be only diseases of aging. In this article, I will outline our perspective and some of the approaches that my laboratory has begun to take to characterize the molecular basis of cerebral asymmetry. Most of these data are preliminary and the models presented are highly speculative, reflecting the primitive stage of work defining the molecular basis of cerebral asymmetry.