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Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer's disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.

Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.

Purpose: Information and communication technology (ICT)-based training devices for older adults' care related to dementia are being developed to enhance older adults' cognitive functions. Older adults who require bicycle training devices can improve muscle strength and balance of lower limbs by continuously contracting and relaxing lower-limb muscles and improving cognitive function to prevent dementia. This study was conducted to investigate the effects of an ICT-based multicomponent program on body composition and cognitive function in older adults. Patients and Methods: In a randomized controlled intervention test on 20 people over the age of 60 (exercise group: n = 10; control: n = 10), the multicomponent program was applied to the exercise group twice per week, once per day for 12 weeks, at 30 min per session, whereas the control group was advised to maintain their usual daily activities. Results: Comparing body composition changes and cognitive function changes before and after intervention exhibited statistically significant differences in skeletal muscle mass (P=0.01) and modified Alzheimer's disease assessment scale–cognitive score (P=0.01) between the two groups. Conclusion: It can be difficult to be engaged in a simple repetitive exercise program. Therefore, to meet older adults' interests and expectations, a customized ICT-based multicomponent program, which can improve body composition and cognitive function in older adults and is believed to help prevent dementia, is recommended. Trial Registration: UMIN000042129 (https://www.umin.ac.jp/english/). [ABSTRACT FROM AUTHOR]

Abstract: Structural optimization of the prior lead 3 led to the small molecular (d)-leucinamides with potent modulating activity and Notch-sparing selectivity on the proteolytic processing of amyloid-β precursor proteins. The N-(R)-epoxypropyl analog 10c exhibited potent γ-secretase modulation compared to DAPT and showed substantial substrate selection for APP cleavage over Notch cleavage, while N-(2-fluoro)benzyl analog 10e showed the most potent γ-secretase inhibition with dull selectivity. The exceptional suppression of ERK-mediated activation suggested that these potent γ-secretase modulators may adapt an alternative pathway to prominently induce the differential inhibition of C99 cleavage by γ-secretase. [Copyright &y& Elsevier]

Abstract: A type of new 1,2,3,4-tetrahydroisoquinoline derivatives was synthesized via concise procedure from commercially available tetrahydroisoquinoline. These derivatives were delicately designed to possess propargyl-related pharmacophores simulated with a monoamine oxidase inhibitor rasagiline. We investigated the effect of these synthetic tetrahydroisoquinoline derivatives on the regulation of proteolytic processing of amyloid precursor protein (APP) by an ERK-dependent signaling pathway. Additionally, these compounds were also evaluated on the prevention of the proteolytic processing of C99 as γ-secretase inhibitors by using a highly efficient cell-based reporter gene assay for γ-secretase. The results suggested that certain compounds might be explored to possess both sAPPα-releasing stimulation and γ-secretase inhibitory potency, which may reflect the synergetic potential of neuroprotective activities for the treatment of Alzheimer’s disease as they possessed both ERK activation and inhibition of amyloidogenic Aβ release. [Copyright &y& Elsevier]

Abstract: Previous studies have demonstrated that the ERK MAPK acts as a negative regulator of γ-secretase. Here, we demonstrate that the activation of ERK MAPK pathway by sodium selenite can inhibit endogenous γ-secretase activity. Consistently, the γ-secretase-mediated production of amyloid-β (Aβ) was dramatically attenuated by sodium selenite in a temporal manner. To substantiate the functional role of ERK MAPK in the regulation of γ-secretase, we demonstrate that cells transfected with the wild-type MEK1 and a constitutively active mutant of MEK1 also displayed a significant attenuation of γ-secretase activity. The active purified ERK1/2 can significantly reduce the γ-secretase-mediated processing of C99, possibly through inducing alterations in the phosphorylation of both nicastrin and presenilin-1. Together, our data suggest that the selenite-elicited ERK activation could effectively reduce Aβ production, supporting that selenium compounds could represent a novel class of nutrient supplements to slow down the progression of Alzheimer''s disease. [Copyright &y& Elsevier]