PrPC as a Transducer of Physiological and Pathological Signals

After the discovery of prion phenomenon, the physiological role of the cellular prion protein (PrPC) remained elusive. In the past decades, molecular and cellular analysis has shed some light regarding interactions and functions of PrPC in health and disease. PrPC, which is located mainly at the plasma membrane of neuronal cells attached by a glycosylphosphatidylinositol (GPI) anchor, can act as a receptor or transducer from external signaling. Although the precise role of PrPC remains elusive, a variety of functions have been proposed for this protein, namely, neuronal excitability and viability. Although many issues must be solved to clearly define the role of PrPC, its connection to the central nervous system (CNS) and to several misfolding-associated diseases makes PrPC an interesting pharmacological target. In a physiological context, several reports have proposed that PrPC modulates synaptic transmission, interacting with various proteins, namely, ion pumps, channels, and metabotropic receptors. PrPC has also been implicated in the pathophysiological cell signaling induced by β-amyloid peptide that leads to synaptic dysfunction in the context of Alzheimer’s disease (AD), as a mediator of Aβ-induced cell toxicity. Additionally, it has been implicated in other proteinopathies as well. In this review, we aimed to analyze the role of PrPC as a transducer of physiological and pathological signaling.

Prediction of Cerebral Amyloid Pathology Based on Plasma Amyloid and Tau Related Markers

Background and Purpose: Pyroglutamate-modified β-amyloid peptide (AβpE) is crucial for AD pathophysiological process. The potential associations of plasma AβpE and total tau (t-tau) with brain Aβ burden and cognitive performance remain to be clarified.Methods: Forty-six subjects with unimpaired cognition, mild cognitive impairment, or very mild dementia were enrolled. Plasma levels of AβpE3−40, t-tau, and Aβ42 were quantified by immunomagnetic reduction (IMR) assays. We analyzed individual and combined biomarker correlations with neuropsychological scores and Aβ positivity determined by 18F-florbetapir positron emission tomography (PET).Results: Both plasma AβpE3−40 levels and AβpE3−40/t-tau ratios correlated negatively with short-term memory and global cognition scores, while correlating positively with PET standardized uptake value ratios (SUVRs). Among the biomarkers analyzed, the combination of AβpE3−40 in a ratio with t-tau had the best discriminatory ability for Aβ PET positivity. Likewise, logistic regression analysis showed that AβpE3−40/t-tau was a highly robust predictor of Aβ PET positivity after controlling for relevant demographic covariates.Conclusion: Plasma AβpE3−40/t-tau ratios correlate with cognitive function and cerebral Aβ burden. The suitability of AβpE3−40/t-tau as a candidate clinical biomarker of AD pathology in the brain should be examined further in larger studies.

EK100 and Antrodin C Improve Brain Amyloid Pathology in APP/PS1 Transgenic Mice by Promoting Microglial and Perivascular Clearance Pathways

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid peptide (Aβ). There are currently no drugs that can successfully treat this disease. This study first explored the anti-inflammatory activity of seven components isolated from Antrodia cinnamonmea in BV2 cells and selected EK100 and antrodin C for in vivo research. APPswe/PS1dE9 mice were treated with EK100 and antrodin C for one month to evaluate the effect of these reagents on AD-like pathology by nesting behavior, immunohistochemistry, and immunoblotting. Ergosterol and ibuprofen were used as control. EK100 and antrodin C improved the nesting behavior of mice, reduced the number and burden of amyloid plaques, reduced the activation of glial cells, and promoted the perivascular deposition of Aβ in the brain of mice. EK100 and antrodin C are significantly different in activating astrocytes, regulating microglia morphology, and promoting plaque-associated microglia to express oxidative enzymes. In contrast, the effects of ibuprofen and ergosterol are relatively small. In addition, EK100 significantly improved hippocampal neurogenesis in APPswe/PS1dE9 mice. Our data indicate that EK100 and antrodin C reduce the pathology of AD by reducing amyloid deposits and promoting nesting behavior in APPswe/PS1dE9 mice through microglia and perivascular clearance, indicating that EK100 and antrodin C have the potential to be used in AD treatment.

New RNA-Based Breakthroughs in Alzheimer’s Disease Diagnosis and Therapeutics

Dementia is described as the fifth leading cause of death worldwide and Alzheimer’s disease (AD) is recognized as the most common, causing a huge impact on health costs and quality of patients’ lives. The main hallmarks that are commonly associated with the pathologic process are amyloid deposition, pathologic Tau phosphorylation and neurodegeneration. It is still unclear how these events are linked to the disease progression, due to the complex pathologic mechanisms. Nevertheless, several hypotheses have been proposed for a better understanding of AD. The AD diagnosis is performed by using a combination of several tools to detect β-amyloid peptide (Aβ) deposits and modifications in cognitive performance, sometimes being expensive and invasive. In the treatment field, there is still an absence of effective treatments to delay or stop the progression of the disease, with most of the approved drugs used to relieve symptoms, and all of them with significant adverse side effects. Considering all limitations, the need to establish new and more effective diagnostic and therapeutic strategies becomes clear. This review aims not only to describe the disease and its impact but also to collect the currently available diagnostic and therapeutic strategies, highlighting new promising RNA-based strategies for AD.

Beta Amyloid, Tau Protein, and Neuroinflammation: An Attempt to Integrate Different Hypotheses of Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is a neurodegenerative disease that inevitably results in dementia and death. Currently, there are no pathogenetically grounded methods for the prevention and treatment of AD, and all current treatment regimens are symptomatic and unable to significantly delay the development of dementia. The accumulation of β-amyloid peptide (Aβ), which is a spontaneous, aggregation-prone, and neurotoxic product of the processing of signaling protein APP (Amyloid Precursor Protein), in brain tissues, primarily in the hippocampus and the frontal cortex, was for a long time considered the main cause of neurodegenerative changes in AD. However, attempts to treat AD based on decreasing Aβ production and aggregation did not bring significant clinical results. More and more arguments are arising in favor of the fact that the overproduction of Aβ in most cases of AD is not the initial cause, but a concomitant event of pathological processes in the course of the development of sporadic AD. The concept of neuroinflammation has come to the fore, suggesting that inflammatory responses play the leading role in the initiation and development of AD, both in brain tissue and in the periphery. The hypothesis about the key role of neuroinflammation in the pathogenesis of AD opens up new opportunities in the search for ways to treat and prevent this socially significant disease.

Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-amyloid Assemblies

The β-amyloid peptide (Aβ) is the main constituent of senile plaques, a typical hallmark of Alzheimer’s disease (AD). Monomeric Aβ is generated through sequential processing of the amyloid precursor protein (APP), with a final step involving γ-secretase activity. In AD, Aβ monomers assemble in oligomers and ultimately fibrils depositing in plaques. Importantly, Aβ toxicity appears related to its soluble oligomeric intermediates. In particular, recombinant Aβ studies described Aβ hexamers as critical oligomeric nuclei. We recently identified hexameric Aβ assemblies in a cellular model, and revealed their ability to enhance recombinant Aβ aggregation in vitro. Here, we assessed the contribution of similar hexameric-like Aβ assemblies to the development of amyloid pathology. We report their early presence in both transgenic mice brains exhibiting human Aβ pathology and cerebrospinal fluid of AD patients, suggesting hexameric Aβ as a putative novel AD biomarker. Using isolated cell-derived hexameric Aβ, we report the potential of these assemblies to seed other human Aβ species, resulting in neuronal toxicity in vitro and amyloid deposition aggravation in vivo. In order to identify key contributors to their formation in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in the formation of hexameric-like Aβ assemblies. As catalytic subunits of the γ-secretase complex, PS1 and PS2 can differentially participate in Aβ generation. Using CRISPR-Cas9-modified neuronal-like cell lines knockdown for each of the two presenilins, we present experimental evidence suggesting a direct link between the PS2-dependent pathway and the release of hexameric-like Aβ assemblies in extracellular vesicles.