S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (Aβ) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in Aβ-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNG treatment on memory deficit and Aβ accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, we employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and Aβ-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3 months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral Aβ plaque deposition, insoluble Aβ levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce Aβ loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aβ neuropathology, indicating that HNG has potential as a pharmacotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD.

Zhang W ，Zhang W ，Li Z ，Hao J ，Zhang Z ，Liu L ，Mao N ，Miao J ，Zhang L ... -  《-》

Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

Amyloid-beta peptide (Aβ) is believed to be central in the pathogenesis of Alzheimer's disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aβ pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aβ pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aβ1-40 and Aβ1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aβ1-40 and Aβ1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aβ plaque load and fibrillar Aβ plaque load), total Aβ levels (Aβ1-40 and Aβ1-42), as well as insoluble Aβ levels (Aβ1-40 and Aβ1-42). Stepwise multiple regression analysis identified hippocampal soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aβ in middle-aged APPswe/PS1dE9 mice, in which soluble Aβ levels are only a tiny fraction of the amount of total Aβ levels. Consequently, our findings provide further evidence that soluble Aβ might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble Aβ species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aβ.

Zhang W ，Hao J ，Liu R ，Zhang Z ，Lei G ，Su C ，Miao J ，Li Z ... -  《-》

Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive cognitive deficits and synaptic dysfunction. Over the last decade phosphodiesterase inhibitors (PDEIs) have received increasing attention as putative cognition enhancers and have been suggested as a novel treatment strategy for AD. Given their ability to prevent hydrolysis of cAMP and/or cGMP, they can stimulate the cAMP/protein kinase A (PKA)/cAMP element-binding protein (CREB) and cGMP/PKG/CREB pathway to enhance synaptic transmission by increasing CREB phosphorylation (pCREB) and brain-derived neurotrophic factor (BDNF) transcription. Based on previous research, we hypothesized that chronic PDE2I treatment would improve AD-related cognitive deficits, by decreasing amyloid-β (Aβ) plaque load, enhancing pCREB and BDNF levels and increasing synaptic density in the hippocampus of 8-month-old APPswe/PS1dE9 mice. Results indicated that chronic PDE2I treatment could indeed improve memory performance in APPswe/PS1dE9 mice, without affecting anxiety, depressive-like behavior or hypothalamus-pituitary-adrenal axis regulation. However, no treatment effects were observed on Aβ plaque load, pCREB or BDNF concentrations, or presynaptic density in the hippocampus, suggesting that other signaling pathways and/or effector molecules might be responsible for its cognition-enhancing effects. Presynaptic density in the stratum lucidum of the CA3 subregion was significantly higher in APPswe/PS1dE9 mice compared to WT controls, possibly reflecting a compensatory mechanism. In conclusion, PDEs in general, and PDE2 specifically, could be considered as promising therapeutic targets for cognition enhancement in AD, although the underlying mechanism of action remains to be elucidated. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Sierksma AS ，Rutten K ，Sydlik S ，Rostamian S ，Steinbusch HW ，van den Hove DL ，Prickaerts J ... -  《-》

An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.

Rodríguez Cruz Y ，Strehaiano M ，Rodríguez Obaya T ，García Rodríguez JC ，Maurice T ... -  《-》

Morin reverses neuropathological and cognitive impairments in APPswe/PS1dE9 mice by targeting multiple pathogenic mechanisms.

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive cognitive impairment and multiple distinct neuropathological features. Currently, there are no available therapies to delay or block the disease progression. Thus, the disease-modifying therapies are urgent for this devastating disorder by simultaneously targeting multiple distinct pathological processes. Morin, a natural bioflavonoid, have been shown to be strongly neuroprotective in vitro and in vivo. In this study, we first investigated the disease-modifying effects of chronic morin administration on the neuropathological and cognitive impairments in APPswe/PS1dE9 double transgenic mice. Our results showed that chronic morin administration prevented spatial learning and memory deficits in the APPswe/PS1dE9 mice. Morin treatment in the APPswe/PS1dE9 mice markedly reduced cerebral Aβ production and Aβ plaque burden via promoting non-amyloidogenic APP processing pathway by increasing ADAM10 expression, inhibiting amyloidogenic APP processing pathway by decreased BACE1 and PS1 expression, and facilitating Aβ degradation by enhancing Aβ-degrading enzyme expression. In addition, we also found that morin treatment in the APPswe/PS1dE9 mice markedly decreased tau hyperphosphorylation via its inhibitory effect on CDK5 signal pathway. Furthermore, morin treatment in the APPswe/PS1dE9 mice markedly reduced the activated glial cells and increased the expression of synaptic markers. Collectively, our findings demonstrate that chronic morin treatment restores cognitive functions and reverses multiple distinct neuropathological AD-like hallmarks in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective actions and neurobiological mechanisms of morin against AD, suggesting that morin is a potently promising disease-modifying agent for treatment of AD.

Du Y ，Qu J ，Zhang W ，Bai M ，Zhou Q ，Zhang Z ，Li Z ，Miao J ... -  《-》