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Author(s): Michael T. Lin [1]; M. Flint Beal (corresponding author) [1] Neurodegenerative diseases are a heterogeneous group of disorders characterized by gradually progressive, selective loss of anatomically or physiologically related [...]

Abstract Background Hashimoto’s encephalopathy is a poorly understood syndrome consisting of heterogeneous neurological symptoms and high serum antithyroid antibody titers, typically responding to steroids. More clinical series studies are required to characterize the clinical, laboratory and imaging features, and outcomes, especially in the Chinese population. Methods We analyzed the clinical, laboratory, and imaging features and outcomes of thirteen consecutive patients with Hashimoto’s encephalopathy diagnosed in Xuan Wu Hospital, Beijing from 2005 to 2010 retrospectively. Results Cognitive impairment (84.6%) and psychiatric symptoms (38.5%) were the most frequent symptoms. Seizures (30.8%) and myoclonus (7.7%) were less common than previously described. Three (23.1%) patients showed abnormal signals in hippocampus or temporal lobe, which were believed related to their memory disorders or seizures. MRI changes showed resolution paralleling clinical improvement in one patient. Among eight patients who received steroid therapy, five patients recovered, one patient improved with residual deficits, and two patients relapsed or had no effect. Among five non-steroid treated patients, three patients experienced stable remission with antiepileptic drugs or general neurotrophic therapy, and two patients experienced continuous deterioration. Conclusions Most patients with Hashimoto’s encephalopathy showed good response to steroids. Some patients improved without steroid therapy. Considering its reversible course, we recommend that Hashimoto’s encephalopathy should always be in the differential diagnosis while evaluating disorders of the central nervous system.

Author(s): Michael T Lin [1]; M Flint Beal [1] Although the amyloid plaques characteristic of Alzheimer disease consist of extracellular aggregates of the toxic amyloid-[beta] peptide, researchers are increasingly recognizing [...]

Background: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD). Methodology/Principal Findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Aβ1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR. Conclusions/Significance: These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD. [ABSTRACT FROM AUTHOR]

A central question in Alzheimer's disease research is what role synaptic activity plays in the disease process. Synaptic activity has been shown to induce β-amyloid peptide release into the extracellular space, and extracellular β-amyloid has been shown to be toxic to synapses. We now provide evidence that the well established synaptotoxicity of extracellular β-amyloid requires β-secretase processing of amyloid precursor protein. Recent evidence supports an important role for intraneuronal β-amyloid in the pathogenesis of Alzheimer's disease. We show that synaptic activity reduces intraneuronal β-amyloid and protects against β-amyloid-related synaptic alterations. Wedemonstrate that synaptic activity promotes the transport of the amyloid precursor protein to synapses using live cell imaging, and that the protease neprilysin is involved in reduction of intraneuronal β-amyloid with synaptic activity. [ABSTRACT FROM AUTHOR]

Multiple lines of evidence implicate β-amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Aβ is involved remain unclear. Addition of Aβ to the extracellular space can be neurotoxic. Intraneuronal Aβ42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Aβ42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Aβ42 with time in culture. Furthermore, we demonstrate that Aβ42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Aβ42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects the anterior horn cells of the spinal cord and cortical motor neurons. A pathophysiological role for mtDNA mutations was postulated based on the finding that cybrids obtained from mitochondria of sporadic ALS patients exhibited impaired respiratory chain activities, increased free radical scavenging enzymes, and altered calcium homeostasis. To date, however, no distinct mtDNA alterations associated with ALS have been reported. Therefore, we reexamined the hypotheses that mtDNA mutations accumulate in ALS and that cybrids generated from ALS patients’ blood have impaired mitochondrial respiration. Cybrid cell lines were generated from 143B osteosarcoma ρ0 cells and platelet mitochondria of sporadic ALS patients or age-matched controls. We found no statistically significant differences in mitochondrial respiration between ALS and control cybrids, even when the electron transport chain was stressed with low concentrations of respiratory chain inhibitors. Mitochondrial respiratory chain enzyme activities were also normal in ALS cybrids, and there was no increase in free radical production. Therefore, we showed that mtDNA from platelets of ALS patients was able to restore normal respiratory function in ρ0 cells, suggesting that the presence of mtDNA mutations capable of affecting mitochondrial respiration was unlikely. [Copyright &y& Elsevier]