Neurodegenerative Processes Research Articles

Intranasal administration of GRP78 protein (HSPA5) counteracts the neurodegeneration in the locus coeruleus in a model of chronic sleep restriction in rats

Chronic sleep restriction (sleep less than 6 hours per day) due to the workload and a decrease in sleep quality is an endemic disease in modern society. Chronic sleep deprivation causes serious neuropsychiatric disorders associated with irreversible neurodegenerative changes in the brain. The search for pharmacological agents that can reduce the risk of neurodegeneration as a result of chronic sleep loss is an urgent task issue for biomedicine. Intranasal administration of glucose-regulated 78 kDa heat shock protein (GRP78) has a neuroprotective effect in a rat model of Parkinson´s disease. The neuroprotective potential of intranasally administered GRP78 in chronic sleep deprivation has not been previously studied. The aim of the study is to find out whether preventive intranasal administration of GRP78 is able to weaken and/or stop the process of neurodegeneration in the locus coeruleus in the model of chronic sleep restriction (SR) in rats. The study was conducted on 6 months old male Wistar rats. For sleep deprivation, a validated method of a swinging platform was used in the mode: 3 hours of sleep deprivation and 1 hour of rest continuously for 5 days. Recombinant human protein GRP78 was administered intranasally two days before the start of SR and during 5 days of SR. Cellular and molecular changes in the locus coeruleus during SR and during the administration of GRP78 were studied using immunohistochemistry and Western blotting. It was shown that chronic SR leads to the degeneration of 30% of noradrenergic neurons in the locus coeruleus, that was associated with an increase in the levels of activated caspases-3 and 9. This indicates the development of apoptosis along the mitochondrial pathway. No signs of reactive microgliosis were found in the model of chronic SR in rats. We have demonstrated that intranasally administered GRP78 penetrates and accumulates in the neurons of the locus coeruleus, GRP78 counteracts the death of neurons along the path of apoptosis. The data obtained allows to consider GRP78 as a potential neuroprotective agent for the prevention of pathological consequences of chronic sleep deprivation.

In situ assessment of neuroinflammatory cytokines in different stages of ovine natural prion disease.

According to the neuroinflammatory hypothesis, a cytokine-mediated host innate immune response may be involved in the mechanisms that contribute to the process of neurodegeneration. Specifically, regarding prion diseases, some experimental murine models have evidenced an altered profile of inflammatory intermediaries. However, the local inflammatory response has rarely been assessed, and never in tissues from different natural models throughout the progression of neurodegeneration. The aim of this study was to use immunohistochemistry (IHC) to in situ assess the temporal protein expression of several cytokines in the cerebellum of sheep suffering from various clinical stages of scrapie. Clear changes in the expression of most of the assessed markers were observed in the affected sheep compared to the healthy control sheep, and from different stages. In summary, this preliminary IHC study focusing in the Purkinje cell layer changes demonstrate that all cytokines or respective receptors studied (IL-1, IL-1R, IL-2R, IL-6, IL-10R, and TNFαR) except for IFNγR are disease-associated signaling proteins showing an increase or decrease in relation to the progression of clinical disease. In the future, this study will be extended to other inflammatory mediators and brain regions, focusing in particular on the release of these inflammatory mediators by astroglial and microglial populations.

Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences.

Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed.

Differentiating neurodegenerative diseases based on EEG complexity

Neurodegenerative diseases are common causes of impaired mobility and cognition in the elderly. Among them, tauopathies and α-synucleinopathies were considered. The neurodegenerative processes and relative differential diagnosis were addressed through a qEEG non-linear analytic method. Study aims were to test accuracy of the power law exponent β applied to EEG in differentiating neurodegenerative diseases and to explore differences in neuronal connectivity among different neurodegenerative processes based on β. N = 230 patients with a diagnosis of tauopathy or α-synucleinopathy and at least one artifact-free EEG recording were selected. Periodogram was applied to EEG signal epochs from continuous recordings. Power law exponent β was determined by the slope of the signal power spectrum versus frequency in logarithmic scale. A data-driven clustering based on β values was performed to identify independent subgroups. Data-driven clustering based on β differentiated tauopathies (overall lower β values) from α-synucleinopathies (higher β values) with high sensitivity and specificity. Tauopathies also presented lower values in the correlation coefficients matrix among frontal sites of recording. In conclusion, significant differences in β values were found between tauopathies and α-synucleinopathies. Hence, β is proposed as a possible biomarker of differential diagnosis and neuronal connectivity.

The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.

Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.

Systemic Innate Immune System Restoration as a Therapeutic Approach for Neurodegenerative Disease: Effects of NP001 on Amyotrophic Lateral Sclerosis (ALS) Progression.

Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival. Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival. The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.

Axon guidance genes are regulated by TDP-43 and RGNEF through long-intron removal.

Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons.

Triple Crown: A Single Autopsy Case with Alzheimer’s Disease, Parkinson’s Disease, and Progressive Supranuclear Palsy

Abstract Introduction/Objective Neurodegenerative diseases such as Alzheimer’s Disease(AD), Idiopathic Parkinson’s disease (PD), and Progressive Supranuclear Palsy (PSP), manifest with progressive cognitive and motor deterioration. While each condition traditionally presents distinct clinical features, overlapping symptoms among them make antemortem clinical diagnose less accurate. Concomitant proteinopathies are frequent among neurodegenerative diseases. Here, we report a single autopsy case demonstrating the simultaneous presence of PSP, PD and AD. Methods/Case Report A 70- year- old male, with dementia and a familial history of progressive supranuclear palsy in his brother, underwent autopsy due to concern for progressive supranuclear palsy. The histopathological examination revealed the presence of “ C” age- related plaque score providing definite diagnosis of Alzheimer’s disease. Immunohistochemistry studies on brain sections revealed the presence of Tau positive globose tangles and neurites indicating progressive supranuclear palsy. Furthermore, alpha-synuclein positivity was observed for Lewy bodies and Lewy neurites, confirming idiopathic Parkinson’s disease. Results (if a Case Study enter NA) NA Conclusion While coexisting neurodegenerative diseases with different proteinopathies have been well documented, this case represents the first report providing pathological confirmation of the simultaneous presence of Alzheimer’s Disease, Parkinson’s Disease, and progressive supranuclear palsy in a single patient. These unique findings underscore the complexity of neurodegenerative processes and highlights the importance of comprehensive diagnostic evaluation in patients presenting with overlapping clinical symptoms. These findings hold significant potential to contribute further in the field.

Acute and long-term SARS-CoV-2 infection and neurodegeneration processes—circulus vitiosus

The global pandemic of COVID-19 caused by SARS-CoV-2 has had a devastating impact. Although many survived the acute effects of the pandemic, a significant number of survivors, including those with only mild symptoms, are now experiencing a prolonged and debilitating post-viral syndrome known as LC/PASC (long COVID/post-acute sequelae of SARS-CoV-2). Typical symptoms of LC/PASC include fatigue, breathlessness, chest pain, impaired cognition, difficulty sleeping, fever and gastrointestinal symptoms. Anxiety and depression can also last for weeks to months and range from mild to disabling. The association between neuropsychiatric symptoms and SARS-CoV-2 infection raises questions about the possible routes of SARS-CoV-2 entry to the central nervous system (CNS) and long-term effects of the virus on the CNS, their molecular basis, and the potential risk of neuronal damage associated with the subsequent development of neurodegenerative diseases.

A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

With the aging of the population, the incidence of Alzheimer's disease (AD) has increased dramatically, causing severe medical, care, and economic burdens on society and families. The efficacy of rivastigmine hydrogen tartrate (RHT), the first-line clinical treatment, is severely limited by the complex and multiple pathogenesis of AD and low brain bioavailability caused by the blood-brain barrier (BBB). Confronting such two bottlenecks, the development of multi-target agents encapsulated BBB-bypassing drug delivery systems offer tremendous therapeutics possibilities for AD. In this study, a tailored phytosomes based nose-to-brain drug delivery system with appropriate plume was successfully designed and developed. On the one hand, Ginseng RG3-based phytosomes loaded with RHT was designed for the co-delivery of GRg3 and RHT, achieving the multi-target pharmacology for AD treatment. On the other hand, a tailored nose-to-brain drug delivery system was established for the satisfactory nose-to-brain delivery efficiency, avoiding the obstacle of BBB through bypassing it. In the pharmacodynamic study based on AD rat model, GRg3@RHT exhibited obviously synergic effect, effectively break the vicious cycle of AD progression, ultimately markedly ameliorating learning and memory ability as well as behavioral dysfunctions, and delaying the neurodegenerative process associated with AD. In addition, the strong correlation of viscosity-droplet size-plume geometry-olfactory deposition was also established, and further proved by the in vivo pharmacokinetic study, which is proposed to provide evidence to enhance nose-to-brain delivery efficiency. This study is anticipated to provide novel insights into AD treatment strategies while offering innovative ideas for drug delivery approaches targeting nervous system disorders.

The Neuroprotective Role of Cyanobacteria with Focus on the Anti-Inflammatory and Antioxidant Potential: Current Status and Perspectives.

Neurodegenerative diseases are linked to the process of neurodegeneration. This can be caused by several mechanisms, including inflammation and accumulation of reactive oxygen species. Despite their high incidence, there is still no effective treatment or cure for these diseases. Cyanobacteria have been seen as a possible source for new compounds with anti-inflammatory and antioxidant potential, such as polysaccharides (sacran), phycobiliproteins (phycocyanin) and lipopeptides (honaucins and malyngamides), which can be interesting to combat neurodegeneration. As a promising case of success, Arthrospira (formerly Spirulina) has revealed a high potential for preventing neurodegeneration. Additionally, advantageous culture conditions and sustainable production of cyanobacteria, which are allied to the development of genetic, metabolic, and biochemical engineering, are promising. The aim of this review is to compile and highlight research on the anti-inflammatory and antioxidant potential of cyanobacteria with focus on the application as neuroprotective agents. Also, a major goal is to address essential features that brand cyanobacteria as an ecoefficient and economically viable option, linking health to sustainability.

Advances in different adult stem cell-derived exosomal non-coding RNAs for the treatment of neurological disorders: a narrative review.

Neurological disorders are being increasingly recognized as major causes of death and disability around the world. Neurological disorders refer to a broad range of medical conditions that affect the brain and spinal cord. These disorders can have various causes, including genetic factors, infections, trauma, autoimmune reactions, or neurodegenerative processes. Each disorder has its own unique symptoms, progression, and treatment options. Optimal communication between interneurons and neuron-glia cells within the homeostatic microenvironment is of paramount importance. Within this microenvironment, exosomes play a significant role in promoting intercellular communication by transferring a diverse cargo of contents, including proteins, lipids, and non-coding RNAs (ncRNAs). Partially, nervous system homeostasis is preserved by various stem cell-derived exosomal ncRNAs, which include circular RNAs (circRNAs), long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs). The diversity of these exosomal ncRNAs suggests their potential to influence multiple pathways and cellular processes within the nervous system. Stem cell-derived exosomes and their ncRNA contents have been investigated for potential therapeutic uses in neurological disorders, owing to their demonstrated capabilities in neuroprotection, neuroregeneration, and modulation of disease-related pathways. The ability of stem cell-derived exosomes to cross the blood-brain barrier makes them a promising delivery vehicle for therapeutic ncRNAs. This review aims to summarize the current understanding of different stem cell-derived exosomal ncRNAs and their therapeutic potential and clinical applications.

Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions.

Oligomeric forms of α-synuclein (α-syn) are critical in the formation of α-synuclein fibrils, exhibiting neurotoxic properties that are pivotal in the pathogenesis of Parkinson's disease (PD). A salient feature of this pathology is the disruption of the protein folding capacity of the endoplasmic reticulum (ER), leading to a perturbation in the ER's protein quality control mechanisms. The accumulation of unfolded or misfolded proteins instigates ER stress. However, the onset of ER stress and the consequent activation of the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-Associated Degradation (ERAD) pathways do not merely culminate in apoptosis when they fail to restore cellular homeostasis. More critically, this condition initiates a cascade of reactions involving ER-related structures and organelles, resulting in multifaceted cellular damage and, potentially, a feedback loop that precipitates neuroinflammation. In this review, we elucidate the interplay between UPR and ERAD, as well as the intricate crosstalk among the ER and other organelles such as mitochondria, lysosomes, and the Golgi apparatus, underscoring their roles in the neurodegenerative process.

Decoding Brain Development and Aging

Abstract The aging process induces a variety of changes in the brain detectable by magnetic resonance imaging (MRI). These changes include alterations in brain volume, fluid-attenuated inversion recovery (FLAIR) white matter hyperintense lesions, and variations in tissue properties such as relaxivity, myelin, iron content, neurite density, and other microstructures. Each MRI technique offers unique insights into the structural and compositional changes occurring in the brain due to normal aging or neurodegenerative diseases. Age-related brain volume changes encompass a decrease in gray matter and an increase in ventricular volume, associated with cognitive decline. White matter hyperintensities, detected by FLAIR, are common and linked to cognitive impairments and increased risk of stroke and dementia. Tissue relaxometry reveals age-related changes in relaxivity, aiding the distinction between normal aging and pathological conditions. Myelin content, measurable by MRI, changes with age and is associated with cognitive and motor function alterations. Iron accumulation, detected by susceptibility-sensitive MRI, increases in certain brain regions with age, potentially contributing to neurodegenerative processes. Diffusion MRI provides detailed insights into microstructural changes such as neurite density and orientation. Neurofluid imaging, using techniques like gadolinium-based contrast agents and diffusion MRI, reveals age-related changes in cerebrospinal and interstitial fluid dynamics, crucial for brain health and waste clearance. This review offers a comprehensive overview of age-related brain changes revealed by various MRI techniques. Understanding these changes helps differentiate between normal aging and pathological conditions, aiding the development of interventions to mitigate age-related cognitive decline and other symptoms. Recent advances in machine learning and artificial intelligence have enabled novel methods for estimating brain age, offering also potential biomarkers for neurological and psychiatric disorders.

Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

The gut microbiota as a link between Alzheimer's disease and obesity.

Alzheimer's disease (AD) is a degenerative disease that causes a progressive decline in memory and thinking skills. Over the past few years, diverse studies have shown that there is no single cause of AD; instead, it has been reported that factors such as genetics, lifestyle, and environment contribute to the pathogenesis of the disease. In this sense, it has been shown that obesity during middle age is one of the most prominent modifiable risk factors for AD. Of the multiple potential mechanisms linking obesity and AD, the gut microbiota (GM) has gained increasing attention in recent years. However, the underlying mechanisms that connect the GM with the process of neurodegeneration remain unclear. Through this narrative review, we present a comprehensive understanding of how alterations in the GM of people with obesity may result in systemic inflammation and affect pathways related to the pathogenesis of AD. We conclude with an analysis of the relationship between GM and insulin resistance, a risk factor for AD that is highly prevalent in people with obesity. Understanding the crosstalk between obesity, GM, and the pathogenesis of AD will help to design new strategies aimed at preventing neurodegeneration.

Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.

A review of proposed mechanisms for neurodegenerative disease.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.

Prion protein prevents the inhibition of large-conductance calcium-activated potassium channel by Tau peptide K18 oligomers

Alzheimer's disease (AD) is a tauopathy characterized by the deposition of amyloid aggregates of hyperphosphorylated Tau protein and amyloid-β peptide (Aβ) in the brain. Nevertheless, a soluble, oligomeric forms of Tau and Aβ are considered to be the most neurotoxic species responsible for neurodegenerative processes in AD. The mechanism of action of these oligomers remains largely unclear. Previously, we demonstrated the inhibition of the large-conductance calcium-activated potassium channel (BKCa) by Aβ. Therefore, in the present study we investigated the effect of Tau protein on the BKCa activity. Furthermore, since prion protein (PrP) interacts with Tau and the N-terminal fragment of PrP, called N1, can be neuroprotective in tauopathies, we checked whether N1 can also act at the level of BKCa channel.In the studies we used monomers, oligomers and amyloid fibrils of aggregation-prone Tau fragment, called K18, carrying tauopathy-associated mutation - deletion of Lys280 (K18Δ280). Additionally, to induce formation of neurotoxic oligomers, K18Δ280 was phosphorylated by protein kinase A (PKA). The activity of the plasma membrane BKCa of hippocampal neurons was recorded using single-channel patch-clamp technique in both inside-out and outside-out modes, exposing the cytosolic or extracellular surface of the membrane, respectively.In the outside-out mode - performing the extracellular application of the neurotoxic oligomers of phosphorylated K18Δ280, we observed a significant and concentration-dependent decrease in the probability of opening (Po) of BKCa. The Po of BKCa was fully recovered after washing the oligomers out. In the case of the inside-out patch-clamp configuration, we found that the Po of BKCa was not affected by the oligomers. In contrast to the oligomers, the monomers and amyloid fibrils of K18Δ280 had no effect on the channel activity, analyzed in inside-out as well as outside-out modes. Noteworthy, upon incubation with N1, the oligomers did not inhibit BKCa channel.The BKCa channel inhibition, dependent on the outside-out membrane orientation, implies specific interaction of the oligomers with the extracellular part of the channel. Moreover, our results suggest that N1 can convert the neurotoxic oligomers of Tau into a form which is not able to inhibit the channel, and indicate novel possible neuroprotective mechanism of PrP action in AD and other tauopathies.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

&lt;p&gt;Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. &lt;/p&gt;&lt;p&gt; Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. &lt;/p&gt;&lt;p&gt; This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.&lt;/p&gt;