Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3-positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long-term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice.

Relationship between Parkinson disease with dementia and dementia with Lewy bodies.

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are considered Lewy body diseases (LBDs). To clarify the relation between PD with dementia (PDD) and DLB, 30 patients with LBD were divided into pathological subtypes according to the consensus guidelines for DLB. Patients with PDD showed neocortical and limbic type of LBD as well as patients with DLB. Dementia had not been noted in 2 patients with neocortical type. Our results indicate that PDD and DLB share a common pathological substrate and that the pathological subtypes of LBD show considerable overlap in clinical manifestations.

Apolipoprotein E receptor 2 is involved in neuritic plaque formation in APP sw mice.

Apolipoprotein E receptor 2 (apoER2) is a receptor for apolipoprotein E containing lipoprotein and also for Reelin. Apolipoprotein E-associated risk of developing Alzheimer's disease (AD) may be related to its binding to and clearance by cell surface receptors, including members of the low-density lipoprotein receptor family. Otherwise there is circumstantial evidence that the Reelin signaling pathway may contribute to neurodegeneration in AD. To investigate the role of apoER2 on amyloid deposition and neurodegeneration in vivo, we examined the presence of apoER2 in the brains of APP sw transgenic mice (Tg2576) using three apoER2 monoclonal antibodies. Our immunohistochemical study revealed that apoER2 was localized in fine granular structure and reactive astrocytes surrounding amyloid plaques. The double labeling immunohistochemistry revealed that this granular structure overlaps synaptophysin-positive dystrophic neurites. These findings indicate that neuronal apoER2 may play a role for amyloid deposition and neuronal degeneration in AD.

Excitatory amino acid transporter 2 associates with phosphorylated tau and is localized in neurofibrillary tangles of tauopathic brains.

Phosphorylated tau (p-tau) is the principal component of neurofibrillary tangles, a pathological hallmark, and likely plays a neurotoxic role in tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We subjected brains from autopsy cases of AD, PSP, and CBD to a variety of immunohistochemical, immunoblotting, and pull-down assays. In this study, we show that excitatory amino acid transporter 2 (EAAT2) preferentially interacted with phosphorylated tau and was localized in neurofibrillary tangles in the brains of such patients. These results strongly indicate that EAAT2 acts in tauopathy-related neurodegeneration, and abnormalities in glutamate transport play an important role in the pathogenesis of tauopathies.

Glial localization of four-repeat tau in atypical progressive supranuclear palsy.

In the present case, a patient in whom limb apraxia and asymmetrical parkinsonism developed suggesting corticobasal degeneration, is reported. Neuropathologic examination revealed numerous tufted astrocytes in the precentral cortex in addition to the characteristic pathologic findings of PSP. Therefore, on the basis of clinicopathologic features, atypical progressive supranuclear palsy was diagnosed. In addition, the brain tissue of the present patient was investigated with an antibody specific for four-repeat tau (4R-tau). In the precentral cortex, numerous tau-positive tufted astrocytes, pretangles, and threads were positive for 4R-tau. Using a confocal microscopy we demonstrated that tufted astrocytes positive for 4R-tau were adjacent to astrocytes positive for GFAP. The present findings suggest that accumulation of four-repeat tau in astrocytes is a degenerative process rather than a reactive process.