Neurodegenerative changes of retina in Parkinson disease

In Parkinson’s disease (PD), some structural changes in the retina have been shown using optical coherence tomography (OCT). Among them most attractive are atrophic changes in retinal nerve fi ber layer (RNFL). However, diagnostic signifi cance of the OCT method in PD remains debatable. Objective: to investigate a thickness of RNFL in Parkinson’s disease patients and to determine the signifi cance of the OCT method in the PD diagnostics. Materials and methods. In PD patients (n = 24) and in a control group (n = 20) OCT was used to study the thickness of RNFL — average, in quadrants and in 10 sectors. Results. In patients with PD thinning of RNFL in the inferior quadrant was revealed (p = 0.009). The sensitivity and specifi city of the method were 56% and 82%, respectively. The thickness of RNFL was not associated with parkinsonian symptoms asymmetry, duration and severity of the disease. In the control group and in PD patients, there was a relationship between the RNFL thickness and age. Conclusion. PD is characterized by atrophic changes in the retina in the form of thinning of RNFL in the inferior quadrant, which confi rms the systemic nature of neurodegenerative pathology in this disease going beyond the substantia nigra and brain tissue. At the same time, the thickness of RNFL showed limited diagnostic value for detecting PD cases.

Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer’s disease (AD) and Parkinson’s disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.

Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death. The relationships among these phenotypes and the underlying mechanisms remain largely unclear. Here, we provide evidence that expression of low level of VPS35-mCherry fusion protein in Vps35Neurod6 mice could diminish the phenotypes in an age-dependent manner. Specifically, we have generated a conditional transgenic mouse line, LSL-Vps35-mCherry, which expresses VPS35-mCherry fusion protein in a Cre-dependent manner. Crossing LSL-Vps35-mCherry with Vps35Neurod6 to obtain TgVPS35-mCherry, Vps35Neurod6 mice prevent the neonatal death and diminish the dendritic morphogenesis deficit and gliosis at the neonatal, but not the adult age. Further studies revealed that the Vps35-mCherry transgene expression was low, and the level of Vps35 mRNA comprised only ~5–7% of the Vps35 mRNA of control mice. Such low level of VPS35-mCherry could restore the amount of other retromer components (Vps26a and Vps29) at the neonatal age (P14). Importantly, the neurodegenerative pathology presented in the survived adult TgVps35-mCherry; Vps35Neurod6 mice. These results demonstrate the sufficiency of low level of VPS35-mCherry fusion protein to diminish the phenotypes in Vps35Neurod6 mice at the neonatal age, verifying a key role of neuronal Vps35 in stabilizing retromer complex proteins, and supporting the view for Vps35 as a potential therapeutic target for neurodegenerative diseases.

The glymphatic system and its role in the development of Alzheimer’s disease

One of the main concepts explaining the development of Alzheimer’s disease is currently the amyloid theory. It was reliably established that the accumulation of the pathological protein amyloid β provokes the launch of a number of pathochemical reactions that ultimately lead to the development of synaptic dysfunction and the formation of cognitive disorders. The protein amyloid β is also synthesized in the brain of people who do not suffer from neurodegenerative pathology. Normally, it is actively removed from the brain. However, the exact mechanisms for maintaining its clearance are not established. The recently discovered glymphatic system claims to be such a component. The present review provides a comprehensive analysis of suggestions that the development of glymphatic system dysfunction contributes to the accumulation of amyloid β and the development of the clinical picture of Alzheimer›s disease.

GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice

The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases.

Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches

Alzheimer’s disease (AD) is a neurodegenerative pathology representing a socioeconomic challenge, however, the complex mechanism behind the disease is not yet fully understood [...]

Alzheimer in Brazil, epidemiology of the last 5 years

Introduction: Alzheimer’s disease (AD) is the most frequent neurodegenerative pathology associated with age, being progressive, insidious and irreversible, whose cognitive and neuropsychiatric manifestations result in an eventual disability. Thus, the interest in evaluating the epidemiological profile of hospitalizations in Brazil, according to age and sex in the period of 5 years. Methods: Ecological and descriptive study. The data collection for this study was based on results obtained through the Health Information (TABNET) and the SUS Hospital Information System (SIH / SUS) in the period from 2016 to 2020. Results: In the period of 5 years, 7,431 admissions for Alzheimer’s were registered, with the highest prevalence in the Southeast, with 4,192 cases (56.41% of total admissions), followed by the South, with 1,727 cases (23.24%). The least incident region was in the North, with 199 cases. There was a predominance of females, with 4,842 cases (65.15%). The most affected age group was between 80 and over, with 4,398 cases, followed by between 70 and 79, with 2,117. From 2016 to 2020, there was a decrease of 19.25% in the number of hospitalizations, however it had a progressive increase until 2019, being the most incident year. Conclusion: The profile was given by a female figure over 80 years old, from the Southeast. As for the progressive increase until 2019, it is necessary to implement measures and policies guiding and welcoming these patients and their families, promoting a better quality of life for the affected population.

Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative pathology characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the physical association between the endoplasmic reticulum (ER) and mitochondria, also referred as mitochondria-associated membranes (MAMs), impacts various cellular housekeeping functions such as phospholipids-, glucose-, cholesterol-, and fatty-acid-metabolism, as well as calcium signaling, which are all altered in AD. Our review describes the physical and functional proteome crosstalk between the ER and mitochondria and highlights the contribution of distinct molecular components of MAMs to mitochondrial and ER dysfunctions in AD progression. We also discuss potential strategies targeting MAMs to improve mitochondria and ER functions in AD.

Space-Dependent Glia–Neuron Interplay in the Hippocampus of Transgenic Models of β-Amyloid Deposition

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.

A Distinct Scenario of a Patient with Parkinson’s Disease and Comorbid Normal Pressure Hydrocephalus

In literature, patients with coexistence of normal pressure hydrocephalus (NPH) and Parkinsons’s disease (PD) have been rarely reported. Herein, I illustrate the evaluation processes of a remarkable patient with PD and comorbid NPH from my experience, which I think may provide crucial perspectives regarding the management problems of these patients. Besides, the patient had also developed bipolar disorder in the follow-up course and extrapyramidal side effects related to antipsychotic medications, which further complicated the treatment process. I think that results of future reports of larger case series including the long-term follow-up of this group of patients with coexisting NPH and PD would provide substantial perspectives regarding the contributory effects of these two pathophysiologies, as well as management, of NPH in these specific patients with neurodegenerative pathology.