Molecular Neurodegeneration 

About: Molecular Neurodegeneration is an academic journal published by BioMed Central. The journal publishes majorly in the area(s): Neurodegeneration & Medicine. It has an ISSN identifier of 1750-1326. It is also open access. Over the lifetime, 1222 publications have been published receiving 69288 citations. The journal is also known as: MN.

The neuropathological diagnosis of Alzheimer's disease.

Abstract: Alzheimer’s disease is a progressive neurodegenerative disease most often associated with memory deficits and cognitive decline, although less common clinical presentations are increasingly recognized. The cardinal pathological features of the disease have been known for more than one hundred years, and today the presence of these amyloid plaques and neurofibrillary tangles are still required for a pathological diagnosis. Alzheimer’s disease is the most common cause of dementia globally. There remain no effective treatment options for the great majority of patients, and the primary causes of the disease are unknown except in a small number of familial cases driven by genetic mutations. Confounding efforts to develop effective diagnostic tools and disease-modifying therapies is the realization that Alzheimer’s disease is a mixed proteinopathy (amyloid and tau) frequently associated with other age-related processes such as cerebrovascular disease and Lewy body disease. Defining the relationships between and interdependence of various co-pathologies remains an active area of investigation. This review outlines etiologically-linked pathologic features of Alzheimer’s disease, as well as those that are inevitable findings of uncertain significance, such as granulovacuolar degeneration and Hirano bodies. Other disease processes that are frequent, but not inevitable, are also discussed, including pathologic processes that can clinically mimic Alzheimer’s disease. These include cerebrovascular disease, Lewy body disease, TDP-43 proteinopathies and argyrophilic grain disease. The purpose of this review is to provide an overview of Alzheimer’s disease pathology, its defining pathologic substrates and the related pathologies that can affect diagnosis and treatment.

Adult hippocampal neurogenesis and its role in Alzheimer's disease

Abstract: The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers

Abstract: Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD), amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Aβ and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. We immunized rabbits with a morphologically homogeneous population of Aβ42 fibrils. The resulting immune serum (OC) specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 × G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type II diabetes, demonstrating its generic specificity for amyloid fibrils. Since the fibril specific antibodies are conformation dependent, sequence-independent, and recognize epitopes that are distinct from those present in prefibrillar oligomers, they may have broad utility for detecting and characterizing the accumulation of amyloid fibrils and fibrillar type oligomers in degenerative diseases.

Exosomal cell-to-cell transmission of alpha synuclein oligomers

Abstract: Aggregation of alpha-synuclein (αsyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson’s disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of αsyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted αsyn across membranes. The aim of this study is to characterize the transcellular spread of αsyn oligomers and determine their extracellular location. Using a novel protein fragment complementation assay where αsyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that αsyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated αsyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free αsyn oligomers. Specifically, we determine that αsyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of αsyn oligomers is strongly influenced by autophagic activity. Our data suggest that αsyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of αsyn oligomers is a mechanism whereby cells clear toxic αsyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in αsyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.

Does neuroinflammation fan the flame in neurodegenerative diseases

Abstract: While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases.