Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: the forgotten partner

Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following different insults to the central nervous system including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinating diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with abnormal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein deposits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus signaling their involvement in the disease. Emerging evidence suggests that such deposits in oligodendrocytes are not mere bystanders but rather are associated with functional alterations. Moreover, operative modifications in oligodendrocytes are also detected in the absence of oligodendroglial inclusions in certain diseases. The present review focuses first on general aspects of oligodendrocytes and precursors, and their development and functions, and then introduces and updates alterations and dysfunction of oligodendrocytes in selected neurodegenerative diseases with abnormal protein aggregates such as multiple system atrophy, Lewy body diseases, tauopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration with TDP-43 inclusions (TDP-43 proteinopathies), and Creutzfeldt-Jakob´s disease as a prototypical human prionopathy

Sisyphus In Neverland

The study of life and living organisms and the way in which these interact and organize to form social communities have been central to my career. I have been fascinated by biology, neurology, and neuropathology, but also by history, sociology, and art. Certain current historical, political, and social events, some occurring proximally but others affecting people in apparently distant places, have had an impact on me. Epicurus, Seneca, and Camus shared their philosophical positions which I learned from. Many scientists from various disciplines have been exciting sources of knowledge as well. I have created a world of hypothesis and experiments but I have also got carried away by serendipity following unexpected observations. It has not been an easy path; errors and wanderings are not uncommon, and opponents close to home much more abundant than one might imagine. Ambition, imagination, resilience, and endurance have been useful in moving ahead in response to setbacks. In the end, I have enjoyed my dedication to science and I am grateful to have glimpsed beauty in it. These are brief memories of a Spanish neuropathologist born and raised in Barcelona, EU

The Primary Microglial Leukodystrophies: A Review

Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu-Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic immunological disease

Neuropathology and Neurochemistry of Nonmotor Symptoms in Parkinson's Disease

Parkinson disease (PD) is no longer considered a complex motor disorder characterized by Parkinsonism but rather a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, autonomic failure, cognitive impairment, and psychiatric symptoms. Many of these alterations appear before or in parallel with motor deficits and then worsen with disease progression. Although there is a close relation between motor symptoms and the presence of Lewy bodies (LBs) and neurites filled with abnormal α-synuclein, other neurological alterations are independent of the amount of α-synuclein inclusions in neurons and neurites, thereby indicating that different mechanisms probably converge in the degenerative process. Involvement of the cerebral cortex that may lead to altered behaviour and cognition are related to several convergent factors such as (a) abnormal α-synuclein and other proteins at the synapses, rather than LBs and neurites, (b) impaired dopaminergic, noradrenergic, cholinergic and serotoninergic cortical innervation, and (c) altered neuronal function resulting from reduced energy production and increased energy demands. These alterations appear at early stages of the disease and may precede by years the appearance of cell loss and cortical atrophy

Abnormal expression and distribution of MMP2 at initial stages of Alzheimer's disease-related pathology

Previous studies have shown that metalloproteinases (MMPs) participate in the clearance of amyloid-β (Aβ) in Alzheimer's disease (AD); MMP2 and MMP3 cleave soluble Aβ, and both MMP9 and MT1-MMP are able to degrade soluble and fibrillar forms of Aβ. The present study shows increased expression levels of active MMP2 in the entorhinal cortex at early stages of AD-related pathology (Braak and Braak stages I/II-0 and III/IV-A) as revealed by western blotting and gelatin zymography. Confocal microscopy discloses co-localization of MMP2 and phospho-tau in neurofibrillary tangles and dystrophic neurites. MMP2 has the capacity to cleave recombinant tau in vitro in a dose-dependent manner, consistent with a physiological function of MMP2 in normal tau proteolysis. However, MMP2 does not cleave hyperphosphorylated and dephosphorylated tau from enriched paired helical filament fractions. These observations raise the possibility that accumulation of MMP2 in neurofibrillary tangles and concomitant loss of proteolytic capacity on tau protein is a response geared to eliminating production of toxic truncated tau species in AD brains. Keywords: Alzheimer's disease, metalloproteinases, MMP2, neurofibrillary tangles, ta

White matter alterations in Alzheimer’s disease without concomitant pathologies

Aims: Most individuals with AD neuropathological changes have co-morbidities which have an impact on the integrity of the WM. This study analyses oligodendrocyte and myelin markers in the frontal WM in a series of AD cases without clinical or pathological co-morbidities. Methods: From a consecutive autopsy series, 206 cases had neuropathological changes of AD; among them, only 33 were AD without co-morbidities. WM alterations were first evaluated in coronal sections of the frontal lobe in every case. Then, RT-qPCR and immunohistochemistry were carried out in the frontal WM of AD cases without co-morbidities to analyse the expression of selected oligodendrocyte and myelin markers. Results: WM demyelination was more marked in AD with co-morbidities when compared with AD cases without co-morbidities. Regarding the later, mRNA expression levels of MBP, PLP1, CNP, MAG, MAL, MOG and MOBP were preserved at stages I-II/0-A when compared with middle-aged (MA) individuals, but significantly decreased at stages III-IV/0-C. This was accompanied by reduced expression of NG2 and PDGFRA mRNA, reduced numbers of NG2-, Olig2- and HDAC2-immunoreactive cells and reduced glucose transporter immunoreactivity. Partial recovery of some of these markers occurred at stages V-VI/B-C. Conclusions: The present observations demonstrate that co-morbidities have an impact on WM integrity in the elderly and in AD, and that early alterations in oligodendrocytes and transcription of genes linked to myelin proteins in WM occur in AD cases without co-morbidities. These are followed by partial recovery attempts at advanced stages. These observations suggest that oligodendrocytopathy is part of AD

Potential of microfluidics and lab-on-chip platforms to improve understanding of 'prion-like' protein assembly and behavior

Human aging is accompanied by a relevant increase in age-associated chronic pathologies, including neurodegenerative and metabolic diseases. The appearance and evolution of numerous neurodegenerative diseases is paralleled by the appearance of intracellular and extracellular accumulation of misfolded proteins in affected brains. In addition, recent evidence suggests that most of these amyloid proteins can behave and propagate among neural cells similarly to infective prions. In order to improve understanding of the seeding and spreading processes of these 'prion-like' amyloids, microfluidics and 3D lab-on-chip approaches have been developed as highly valuable tools. These techniques allow us to monitor changes in cellular and molecular processes responsible for amyloid seeding and cell spreading and their parallel effects in neural physiology. Their compatibility with new optical and biochemical techniques and their relative availability have increased interest in them and in their use in numerous laboratories. In addition, recent advances in stem cell research in combination with microfluidic platforms have opened new humanized in vitro models for myriad neurodegenerative diseases affecting different cellular targets of the vascular, muscular, and nervous systems, and glial cells. These new platforms help reduce the use of animal experimentation. They are more reproducible and represent a potential alternative to classical approaches to understanding neurodegeneration. In this review, we summarize recent progress in neurobiological research in 'prion-like' protein using microfluidic and 3D lab-on-chip approaches. These approaches are driven by various fields, including chemistry, biochemistry, and cell biology, and they serve to facilitate the development of more precise human brain models for basic mechanistic studies of cell-to-cell interactions and drug discovery

Delineating the efficacy of a cannabis-based medicine at advanced stages of dementia in a murine model

Previous reports have demonstrated that the combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimer-like phenotype of AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in AβPP/PS1 mice at advanced stages of the disease but are not effective in modifying the Aβ processing or in reducing the glial reactivity associated with aberrant Aβ deposition as occurs when administered at early stages of the disease. The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by Δ9-THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone

Cell signaling in the epileptic hippocampus

La señalización celular que manda sobre la muerte o la supervivencia en el hipocampo epiléptico humano es difícil de identificar a causa del prolongado intervalo entre el comienzo de los síntomas y el muestreo del tejido cerebral dañado para el examen neuropatológico. La inyección intraperitonial del glutamato análogo del ácido kaínico (AK) es una herramienta útil para el análisis de los efectos de convulsiones y el daño excitotóxico en el hipocampo del roedor. El AK actúa sobre los receptores NMDA y AK, mientras que el impacto sobre los receptores AMPA es muy pequeño. Las neuronas del hilio y las neuronas CA3 son dianas primarias del AK, aunque las neuronas gabérgicas que contienen parvoalbúmina son menos vulnerables que las neuronas glutamatérgicas. Las respuestas inmediatas al AK son la inducción de hsp-70, ARNm y la expresión de la proteína HSP-70/72, junto con c-fos y c-jun ARNm, y la expresión de las proteínas c-Fos y c-Jun en el hipocampo, aunque la expresión aumentada de c-Fos y c-Jun no predice la muerte celular o la supervivencia de la misma. Por el contrario, el activador del plasminógeno tisular (tPA) y la vía de señal de la membrana Fas/FasL probablemente tenga un papel facilitador en el seguimiento de la muerte celular por la inyección de AK. La afectación de otras vías permanece controvertida. Un aumento en la expresión de Bas pro-apotótico junto con una reducción en Bcl-2 sugiere apoptosis ayudado por Bax. La activación de la vía mitocondrial incluye el escape del citocromo c al citosol y activación de la cascada caspasa que lleva a la apoptosis. Sin embargo, otros estudios han puesto de relieve la expresión limitada de la caspasa-3, el ejecutor principal de la apoptosis, y la relevancia de necrosis como la forma principal de la muerte celular después de la excitotoxicidad del AK. La activación fosforilación dependiente de varias cinasas, entre ellas MAPK, p38 y JNK/SAPK, y sus sustratos, se ha encontrado en los animales tratados con AK. La expresión disminuida de CREBp se asocia con la muerte celular, mientras que el aumento en ATF-2P y Elk-1P se asocia con la supervivencia celular. Los factores tróficos probablemente no desempeñan un papel significativo en las etapas iniciales del daño hipocampal, pero tienen su importancia en el remodelado de las células granulares y el brote de fibras musgosas a la capa molecular del giro dentado. Esta regeneración anómala , a su vez, facilita el 'reclutamiento' y mantenimiento crónico de las convulsiones

Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model

Activating CB1 cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer's disease (AD). In this study, we evaluated the specific contribution of CB1 receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice. A new mouse strain was generated by crossing APP/PS1 transgenic mice with CB1 knockout mice. Genetic deletion of CB1 drastically reduced the survival of APP/PS1 mice. In spite that CB1 mutant mice bearing the APP/PS1 transgene developed normally, they suddenly died within the first two months of life likely due to spontaneous seizures. This increased mortality could be related to an imbalance in the excitatory/inhibitory transmission in the hippocampus as suggested by the reduced density of inhibitory parvalbumin positive neurons observed in APP/PS1 mice lacking CB1 receptor at 7 weeks of age. We also evaluated the AD-like phenotype of APP/PS1 mice heterozygous for the CB1 deletion at 3 and 6 months of age. The memory impairment associated to APP/PS1 transgene was accelerated in these mice. Neither the soluble levels of Aβ or the density of Aβ plaques were modified in APP/PS1 mice heterozygous for CB1 deletion at any age. However, the reduction in CB1 receptor expression decreased the levels of PSD-95 protein in APP/PS1 mice, suggesting a synaptic dysfunction in these animals that could account for the acceleration of the memory impairment observed. In summary, our results suggest a crucial role for CB1 receptor in the progression of AD-related pathological events