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Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer’s disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2 −/− mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2 +/− mice had significantly more plaque-associated microglia than 5XFAD × TREM2 −/− mice. Nonetheless, AD-tau injected 5XFAD × TREM2 +/− mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2 +/+ mice. Expression profiling revealed that 5XFAD × TREM2 +/− mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2 +/+ and 5XFAD × TREM2 −/− mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2 +/− and 5XFAD × TREM2 −/− mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2 +/− and TREM2 −/− mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.

Mutations in leucine-rich repeat kinase 2 ( LRRK2 ) are one of the most common causes of familial Parkinson’s disease (PD). The most common mutations in the LRRK2 gene induce elevated kinase activity of the LRRK2 protein. Recent studies have also suggested that LRRK2 kinase activity may be elevated in idiopathic PD patients, even in the absence of LRRK2 mutations. LRRK2 is therefore a prime candidate for small molecule kinase inhibitor development. However, it is currently unknown how LRRK2 influences the underlying pathogenesis of PD and how LRRK2 might influence extant pathogenesis. To understand whether LRRK2 inhibition would show some benefit in the absence of LRRK2 mutations, we treated a preclinical mouse model of PD with the potent LRRK2 inhibitor MLi-2. The inhibitor was well-tolerated by mice and dramatically reduced LRRK2 kinase activity. However, LRRK2 inhibition did not reverse motor phenotypes, pathological α-synuclein accumulation or neuron loss. The current study suggests that LRRK2 is not necessary for α-synuclein pathogenesis in this mouse model of PD and that further studies are needed to assess the likely clinical benefit of LRRK2 inhibition in idiopathic PD.

In Lewy body diseases—including Parkinson’s disease, without or with dementia, dementia with Lewy bodies, and Alzheimer’s disease with Lewy body co-pathology 1 —α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments. Distinct strains of misfolded α-synuclein proteins, which aggregate in neurons in Lewy body diseases or in oligodendrocytes in multiple system atrophy, are formed as a consequence of differences between intracellular environments.

Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinsonʼs disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC–MS/MS analyses on soluble α-Syn purified from Parkinsonʼs disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression. Pathological α-synuclein (α-Syn) spreading is critical for the progression of many neurodegenerative diseases. The authors demonstrate that soluble α-Syn post-translational modifications (PTMs) dramatically modulate pathological α-synuclein spreading.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are one of the most common causes of familial Parkinson's disease (PD). The most common mutations in the LRRK2 gene induce elevated kinase activity of the LRRK2 protein. Recent studies have also suggested that LRRK2 kinase activity may be elevated in idiopathic PD patients, even in the absence of LRRK2 mutations. LRRK2 is therefore a prime candidate for small molecule kinase inhibitor development. However, it is currently unknown how LRRK2 influences the underlying pathogenesis of PD and how LRRK2 might influence extant pathogenesis. To understand whether LRRK2 inhibition would show some benefit in the absence of LRRK2 mutations, we treated a preclinical mouse model of PD with the potent LRRK2 inhibitor MLi-2. The inhibitor was well-tolerated by mice and dramatically reduced LRRK2 kinase activity. However, LRRK2 inhibition did not reverse motor phenotypes, pathological [alpha]-synuclein accumulation or neuron loss. The current study suggests that LRRK2 is not necessary for [alpha]-synuclein pathogenesis in this mouse model of PD and that further studies are needed to assess the likely clinical benefit of LRRK2 inhibition in idiopathic PD. Keywords: Leucine-rich repeat kinase 2, pS129, Aggregation, Inhibitor, G2019S, MLi-2

Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with A[beta] plaques in Alzheimer's disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of A[beta] plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of A[beta] plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD x TREM2.sup.-/- mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD x TREM2.sup.+/- mice had significantly more plaque-associated microglia than 5XFAD x TREM2.sup.-/- mice. Nonetheless, AD-tau injected 5XFAD x TREM2.sup.+/- mice showed greatly increased AT8-positive NP tau relative to 5XFAD x TREM2.sup.+/+ mice. Expression profiling revealed that 5XFAD x TREM2.sup.+/- mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD x TREM2.sup.+/+ and 5XFAD x TREM2.sup.-/- mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD x TREM2.sup.+/- and 5XFAD x TREM2.sup.-/- mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2.sup.+/- and TREM2.sup.-/- mice suggest that the former may better model the single copy TREM2 variants associated with AD risk. Keywords: Alzheimer's, Microglia, Pathology, Plaques, Tau

Dopamine dysregulation is implicated in psychiatric disorders such as Schizophrenia, Bipolar Disorder, and Major Depression. These conditions are managed by antipsychotics, which can exert their effects through G-protein-mediated or β-arrestin-mediated signaling pathways, which may each regulate different behavioral responses. While the principles of biased signaling provide an attractive strategy for developing novel therapeutics for psychiatric conditions, older methods for surveying the contributions of β-arrestin pathway to behavior are limited. Therefore, this study sought to use CRISPR-Cas9 to generate a model for exploring whether loss of β-arrestin in a regional and cell-type-specific manner could affect psychomotor, emotional, cognitive, and social behaviors.

In Lewy body diseases--including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology.sup.1--[alpha]-synuclein ([alpha]-Syn) aggregates in neurons as Lewy bodies and Lewy neurites.sup.2. By contrast, in multiple system atrophy [alpha]-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs).sup.3. Here we report that pathological [alpha]-Syn in GCIs and Lewy bodies (GCI-[alpha]-Syn and LB-[alpha]-Syn, respectively) is conformationally and biologically distinct. GCI-[alpha]-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-[alpha]-Syn in seeding [alpha]-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-[alpha]-Syn and LB-[alpha]-Syn show no cell-type preference in seeding [alpha]-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded [alpha]-Syn into a GCI-like strain, highlighting the fact that distinct [alpha]-Syn strains are generated by different intracellular milieus. Moreover, GCI-[alpha]-Syn maintains its high seeding activity when propagated in neurons. Thus, [alpha]-Syn strains are determined by both misfolded seeds and intracellular environments.

ABSTRACT Tau pathology is a diagnostic feature of Alzheimer’s disease (AD) but is also a prominent feature of Parkinson’s disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathology’s initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies. Competing Interest Statement The authors have declared no competing interest.