Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

AbstractIntroductionLoss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study.MethodsWe identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences.ResultsMeta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers.DiscussionThe present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected

Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity.

BackgroundHIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity.MethodsGFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy.ResultsWe found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field.ConclusionsTogether, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations

Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5--implications for dementia with Lewy bodies.

BackgroundIn dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.ResultsWe generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.ConclusionsTogether, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB

The many faces of α-synuclein: from structure and toxicity to therapeutic target

Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism (or mechanisms) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention

Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleonopathies

Objectives: Parkinson’s Disease (PD), Dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA) are neurodegenerative disorders of the aging population characterized by the progressive accumulation of alpha-synuclein. Jointly these disorders have been denominated synucleinopathies and currently no disease modifying treatments are available. Previous in vivo studies in transgenic (tg) mice have shown that active and passive immunization targeting alpha-synuclein ameliorates to some extent deficits and synuclein accumulation, however it’s unknown if combining humoral and cellular immunization might synergize and also reduce inflammation and improve microglial cell mediated synuclein clearance. Methods: PDGF- alpha-synuclein tg mice and control non-tg mice were immunized with: 1) Glucan Particle (GP) adjuvant alone, 2) GP human (hu)- alpha-synuclein (active immunization), 3) GP plus rapamycin and 4) GP plus rapamycin and hu-alpha-synuclein (combined active and humoral) and analyzed by neuropathological and biochemical markers. Results: Compared to tg mice treated with adjuvant alone, mice immunized with GP hu-alpha-synuclein displayed a 30% reduction in alpha-synuclein accumulation. Combined immunotherapy with GP plus rapamycin and hu-alpha-synuclein resulted in 50% reduction in alpha-synuclein accumulation which was accompanied by reduced neuro-inflammation (Iba-1, GFAP, IL6, TNFalpha), phospho and insoluble alpha-synuclein, microglia and astroglia cell numbers, and retention of CD25, FoxP3 and CD4 positive cells. Levels of TGFb1 were also increased. Serological studies showed that active immunization resulted in higher levels of total IgG, IgG1 and IgG2 titers, levels were slightly higher in the combined group. Conclusions: In vivo studies targeting alpha-synuclein support the hypothesis that cellular immunization might enhance the effects of active immunotherapy for the treatment of synucleionopathies

Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

The toxicity of α-synuclein invivo is not well understood. Rockenstein etal. describe an α-synuclein transgenic model expressing the E57K mutant that forms stable oligomers. They show that oligomers accumulate at synapses and that the mutation interferes with synaptic vesicles and is associated with behavioural deficits and neurodegeneratio

Modeling Alzheimer’s disease related phenotypes in the Ts65Dn mouse: impact of age on Aβ, Tau, pTau, NfL, and behavior

IntroductionPeople with DS are highly predisposed to Alzheimer’s disease (AD) and demonstrate very similar clinical and pathological features. Ts65Dn mice are widely used and serve as the best-characterized animal model of DS.MethodsWe undertook studies to characterize age-related changes for AD-relevant markers linked to Aβ, Tau, and phospho-Tau, axonal structure, inflammation, and behavior.ResultsWe found age related changes in both Ts65Dn and 2N mice. Relative to 2N mice, Ts65Dn mice showed consistent increases in Aβ40, insoluble phospho-Tau, and neurofilament light protein. These changes were correlated with deficits in learning and memory.DiscussionThese data have implications for planning future experiments aimed at preventing disease-related phenotypes and biomarkers. Interventions should be planned to address specific manifestations using treatments and treatment durations adequate to engage targets to prevent the emergence of phenotypes