The Na+/Ca2+exchanger in Alzheimer’s disease

As a pivotal player in regulating sodium (Na⁺) and calcium (Ca²⁺) homeostasis and signalling in excitable cells, the Na⁺/Ca²⁺ exchanger (NCX) is involved in many neurodegenerative disorders in which an imbalance of intracellular Ca²⁺ and/or Na⁺ concentrations occurs, including Alzheimer’s disease (AD). Although NCX has been mainly implicated in neuroprotective mechanisms counteracting Ca²⁺ dysregulation, several studies highlighted its role in the neuronal responses to intracellular Na⁺ elevation occurring in several pathophysiological conditions. Since the alteration of Na⁺ and Ca²⁺ homeostasis significantly contributes to synaptic dysfunction and neuronal loss in AD, it is of crucial importance to analyze the contribution of NCX isoforms in the homeostatic responses at neuronal and synaptic levels. Some studies found that an increase of NCX activity in brains of AD patients was correlated with neuronal survival, while other research groups found that protein levels of two NCX subtypes, NCX2 and NCX3, were modulated in parietal cortex of late stage AD brains. In particular, NCX2 positive synaptic terminals were increased in AD cohort while the number of NCX3 positive terminals were reduced. In addition, NCX1, NCX2 and NCX3 isoforms were up-regulated in those synaptic terminals accumulating amyloid-beta (Aβ), the neurotoxic peptide responsible for AD neurodegeneration. More recently, the hyperfunction of a specific NCX subtype, NCX3, has been shown to delay endoplasmic reticulum stress and apoptotic neuronal death in hippocampal neurons exposed to Aβ insult. Despite some issues about the functional role of NCX in synaptic failure and neuronal loss require further studies, these findings highlight the putative neuroprotective role of NCX in AD and open new strategies to develop new druggable targets for AD therapy.     

Dysregulated phosphorylation of Ca(2+) /calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder and the most prevalent senile dementia. The early symptom of memory dysfunction involves synaptic loss, thought to be mediated by soluble amyloid-beta (Aβ) oligomers. These aggregate species target excitatory synapses and their levels correlate with disease severity. Studies in cell culture and rodents have shown that oligomers increase intracellular calcium (Ca(2+)), impairing synaptic plasticity. Yet, the molecular mechanism mediating Aβ oligomers' toxicity in the aged brain remains unclear. Here, we apply quantitative immunofluorescence in human brain tissue from clinically diagnosed mild cognitive impaired (MCI) and AD patients to investigate the distribution of phosphorylated (active) Ca(2+) /calmodulin-dependent protein kinase-α (p(Thr286)CaMKII), a critical enzyme for activity-dependent synaptic remodeling associated with cognitive function. We show that p(Thr286)CaMKII immunoreactivity is redistributed from dendritic arborizations to neural perikarya of both MCI and AD hippocampi. This finding correlates with cognitive assessment scores, suggesting that it may be a molecular read-out of the functional deficits in early AD. Treatment with oligomeric Aβ replicated the observed phenotype in mice and resulted in a loss of p(Thr286)CaMKII from synaptic spines of primary hippocampal neurons. Both outcomes were prevented by inhibiting the phosphatase calcineurin (CaN). Collectively, our results support a model in which the synaptotoxicity of Aβ oligomers in human brain involves the CaN-dependent subcellular redistribution of p(Thr286)CaMKII. Therapies designed to normalize the homeostatic imbalance of neuronal phosphatases and downstream dephosphorylation of synaptic p(Thr286)CaMKII should be considered to prevent and treat early AD.     

Posttranslational modification impact on the mechanism by which amyloid‐β induces synaptic dysfunction

Oligomeric amyloid‐β (Aβ) 1‐42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ have been identified, among which N‐terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms. Here, we show that a prominent isoform, pyroglutamated Aβ3(pE)‐42, induces synaptic dysfunction to a similar extent like Aβ1‐42 but by clearly different mechanisms. In contrast to Aβ1‐42, Aβ3(pE)‐42 does not directly associate with synaptic membranes or the prion protein but is instead taken up by astrocytes and potently induces glial release of the proinflammatory cytokine TNFα. Moreover, Aβ3(pE)‐42‐induced synaptic dysfunction is not related to NMDAR signalling and Aβ3(pE)‐42‐induced impairment of synaptic plasticity cannot be rescued by D1‐agonists. Collectively, the data point to a scenario where neuroinflammatory processes together with direct synaptotoxic effects are caused by posttranslational modification of soluble oligomeric Aβ and contribute synergistically to the onset of synaptic dysfunction in AD.     

Aging‐induced Akt activation involves in aging‐related pathologies and Aβ‐induced toxicity

Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and Aβ42‐expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation‐induced early death and Aβ42‐induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of γ‐secretase. Taken together, this study revealed that Akt is involved in the aging process and Aβ toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.     

Ca2＋失调与阿尔茨海默病发生发展关系的研究进展

阿尔茨海默病（Alzheimer’s disease,AD）是全球老年人中最常见的神经退行性疾病。在对家族性AD的动物模型和个别AD患者死后脑组织的研究中发现,除了A1342水平升高外,神经元内Ca2＋信号失调,并且Ca2＋信号蛋白表达水平也发生了改变。淀粉样蛋白斑、神经元纤维缠结和神经元丢失是AD的后期标志,它们的共同点可能是破坏神经元钙离子信号。细胞内钙离子水平提高在功能上与淀粉样蛋白斑、早老素突变、tau缠结和突触功能障碍相关,基于这些研究,产生了AD的Ca2＋假说。主要介绍神经元内Ca2＋失调与AD的关系以及钙拮抗剂作为AD的潜在治疗方法。     

Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death

Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid β (Aβ) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Aβ impairs mitochondrial dynamics and function. Furthermore, mitochondrial Aβ accumulation has been detected in the AD brain. However, the underlying mechanism of how Aβ affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Aβ accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Aβ(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Aβ(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Aβ(1-42) in HT22 cells using Aβ(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Aβ(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Aβ(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Aβ(1-42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Aβ(1-42) accumulation, which mimics the apoptosis process in exogenous Aβ(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Aβ(1-42) accumulation is the necessary and sufficient condition for Aβ-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Aβ-mediated signaling alterations.     

Structural analysis of the pyroglutamate‐modified isoform of the Alzheimer's disease‐related amyloid‐β using NMR spectroscopy

The aggregation of the Aβ plays a fundamental role in the pathology of AD. Recently, N‐terminally modified Aβ species, pE‐Aβ, have been described as major constituents of Aβ deposits in the brains of AD patients. pE‐Aβ has an increased aggregation propensity and shows increased toxicity compared with Aβ1‐40 and Aβ1‐42. In the present work, high‐resolution NMR spectroscopy was performed to study pE‐Aβ3‐40 in aqueous TFE‐containing solution. Two‐dimensional TOCSY and NOESY experiments were performed. On the basis of NOE and chemical shift data, pE‐Aβ3‐40 was shown to contain two helical regions formed by residues 14–22 and 30–36. This is similar as previously described for Aβ1‐40. However, the secondary chemical shift data indicate decreased helical propensity in pE‐Aβ3‐40 when compared with Aβ1‐40 under exactly the same conditions. This is in agreement with the observation that pE‐Aβ3‐40 shows a drastically increased tendency to form β‐sheet‐rich structures under more physiologic conditions. Structural studies of pE‐Aβ are crucial for better understanding the structural basis of amyloid fibril formation in the brain during development of AD, especially because an increasing number of reports indicate a decisive role of pE‐Aβ for the pathogenesis of AD. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid β (Aβ)‐mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H₂O₂ generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA‐approved drugs with a well‐known profile of brain delivery.     

Aβ and human amylin share a common toxicity pathway via mitochondrial dysfunction

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are leading causes of morbidity and mortality in the elderly. Both diseases are characterized by amyloid deposition in target tissues: aggregation of amylin in T2DM is associated with loss of insulin‐secreting β‐cells, while amyloid β (Aβ) aggregation in AD brain is associated with neuronal loss. Here, we used quantitative iTRAQ proteomics as a discovery tool to show that both Aβ and human amylin (HA) deregulate identical proteins, a quarter of which are mitochondrial, supporting the notion that mitochondrial dysfunction is a common target in these two amyloidoses. A functional validation revealed that mitochondrial complex IV activity was significantly reduced after treatment with either HA or Aβ, as was mitochondrial respiration. In comparison, complex I activity was reduced only after treatment with HA. Aβ and HA, but not the non‐amyloidogenic rat amylin, induced significant increases in the generation of ROS. Co‐incubation of HA and Aβ did not produce an augmented effect in ROS production, again suggesting common toxicity mechanisms. In conclusion, our data suggest that Aβ and HA both exert toxicity, at least in part, via mitochondrial dysfunction, thus restoring their function may be beneficial for both AD and T2DM.     

Interactions of amyloid-β peptides on lipid bilayer studied by single molecule imaging and tracking

The amyloid-β peptides (Aβ40 and Aβ42) feature prominently in the synaptic dysfunction and neuronal loss associated with Alzheimer's disease (AD). This has been proposed to be due either to interactions between Aβ and cell surface receptors affecting cell signaling, or to the formation of calcium-permeable channels in the membrane that disrupt calcium homeostasis. In both mechanisms the cell membrane is the primary cellular structure with which Aβ interacts. Aβ concentrations in human bodily fluids are very low (pM-nM) rendering studies of the size, composition, cellular binding sites and mechanism of action of the oligomers formed in vivo very challenging. Most studies, therefore, have utilized Aβ oligomers prepared at micromolar peptide concentrations, where Aβ forms oligomeric species which possess easily observable cell toxicity. Such toxicity has not been observed when nM concentrations of peptide are used in the experiment highlighting the importance of employing physiologically relevant peptide concentrations for the results to be of biological significance. In this paper single-molecule microscopy was used to monitor Aβ oligomer formation and diffusion on a supported lipid bilayer at nanomolar peptide concentrations. Aβ monomers, the dominant species in solution, tightly associate with the membrane and are highly mobile whereas trimers and higher-order oligomers are largely immobile. Aβ dimers exist in a mixture of mobile and immobile states. Oligomer growth on the membrane is more rapid for Aβ40 than for the more amyloidogenic Aβ42 but is largely inhibited for a 1:1 Aβ40:Aβ42 mixture. The mechanism underlying these Aβ40-Aβ42 interactions may feature in Alzheimer's pathology.     

Interaction of NF-κB and Wnt/β-catenin Signaling Pathways in Alzheimer’s Disease and Potential Active Drug Treatments

The most important neuropathological features of Alzheimer's disease (AD) are extracellular amyloid-β protein (Aβ) deposition, tau protein hyperphosphorylation and activation of neurometabolic reaction in the brain accompanied by neuronal and synaptic damage, and impaired learning and memory function. According to the amyloid cascade hypothesis, increased Aβ deposits in the brain to form the core of the senile plaques that initiate cascade reactions, affecting the synapses and stimulating activation of microglia, resulting in neuroinflammation. A growing number of studies has shown that NF-κB and Wnt/β-catenin pathways play important roles in neurodegenerative diseases, especially AD. In this review, we briefly introduce the connection between neuroinflammation-mediated synaptic dysfunction in AD and elaborated on the mechanism of these two signaling pathways in AD-related pathological changes, as well as their interaction. Based on our interest in natural compounds, we also briefly introduce and conduct preliminary screening of potential therapeutics for AD.

     

Brain injury‐induced proteolysis is reduced in a novel calpastatin‐overexpressing transgenic mouse

The calpain family of calcium‐dependent proteases has been implicated in a variety of diseases and neurodegenerative pathologies. Prolonged activation of calpains results in proteolysis of numerous cellular substrates including cytoskeletal components and membrane receptors, contributing to cell demise despite coincident expression of calpastatin, the specific inhibitor of calpains. Pharmacological and gene‐knockout strategies have targeted calpains to determine their contribution to neurodegenerative pathology; however, limitations associated with treatment paradigms, drug specificity, and genetic disruptions have produced inconsistent results and complicated interpretation. Specific, targeted calpain inhibition achieved by enhancing endogenous calpastatin levels offers unique advantages in studying pathological calpain activation. We have characterized a novel calpastatin‐overexpressing transgenic mouse model, demonstrating a substantial increase in calpastatin expression within nervous system and peripheral tissues and associated reduction in protease activity. Experimental activation of calpains via traumatic brain injury resulted in cleavage of α‐spectrin, collapsin response mediator protein‐2, and voltage‐gated sodium channel, critical proteins for the maintenance of neuronal structure and function. Calpastatin overexpression significantly attenuated calpain‐mediated proteolysis of these selected substrates acutely following severe controlled cortical impact injury, but with no effect on acute hippocampal neurodegeneration. Augmenting calpastatin levels may be an effective method for calpain inhibition in traumatic brain injury and neurodegenerative disorders.     

Focal adhesions regulate Aβ signaling and cell death in Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that results from a loss of synaptic transmission and ultimately cell death. The presenting pathology of AD includes neuritic plaques composed of beta-amyloid peptide (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau, with neuronal loss in specific brain regions. However, the mechanisms that induce neuronal cell loss remain elusive. Focal adhesion (FA) proteins assemble into intracellular complexes involved in integrin-mediated communication between the extracellular matrix and the actin cytoskeleton, regulating many cell physiological processes including the cell cycle. Interestingly, recent studies report that integrins bind to Aβ fibrils, mediating Aβ signal transmission from extracellular sites of Aβ deposits into the cell and ultimately to the nucleus. In this review, we will discuss the Aβ induced integrin/FA signaling pathways that mediate cell cycle activation and cell death.     

Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20‐APP transgenic and wild‐type mice

Alzheimer's disease (AD ) is a neurodegenerative pathology characterized by aggregates of amyloid‐β (Aβ) and phosphorylated tau protein, synaptic dysfunction, and spatial memory impairment. The Wnt signaling pathway has several key functions in the adult brain and has been associated with AD , mainly as a neuroprotective factor against Aβ toxicity and tau phosphorylation. However, dysfunction of Wnt/β‐catenin signaling might also play a role in the onset and development of the disease. J20 APP swInd transgenic (Tg) mouse model of AD was treated i.p. with various Wnt signaling inhibitors for 10 weeks during pre‐symptomatic stages. Then, cognitive, biochemical and histochemical analyses were performed. Wnt signaling inhibitors induced severe changes in the hippocampus, including alterations in Wnt pathway components and loss of Wnt signaling function, severe cognitive deficits, increased tau phosphorylation and Aβ_1–42 peptide levels, decreased Aβ42/Aβ40 ratio and Aβ_1–42 concentration in the cerebral spinal fluid, and high levels of soluble Aβ species and synaptotoxic oligomers in the hippocampus, together with changes in the amount and size of senile plaques. More important, we also observed severe alterations in treated wild‐type (WT ) mice, including behavioral impairment, tau phosphorylation, increased Aβ_1–42 in the hippocampus, decreased Aβ_1–42 in the cerebral spinal fluid, and hippocampal dysfunction. Wnt inhibition accelerated the development of the pathology in a Tg AD mouse model and contributed to the development of Alzheimer's‐like changes in WT mice. These results indicate that Wnt signaling plays important roles in the structure and function of the adult hippocampus and suggest that inhibition of the Wnt signaling pathway is an important factor in the pathogenesis of AD .

Read the Editorial Highlight for this article on page 356 .

     

Bepridil decreases Aβ and calcium levels in the thalamus after middle cerebral artery occlusion in rats

Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and β‐amyloid (Aβ) accumulation. We have previously shown that Aβ and calcium deposition, and β‐secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non‐selective calcium channel blocker bepridil, which also inhibits β‐secretase cleavage of APP, affects thalamic accumulation of Aβ and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27‐day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aβ40, Aβ42 and calcium in the ipsilateral thalamus, as compared with vehicle‐treated MCAO rats. Expression of seladin‐1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin‐1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase‐1‐ or NAD(P)H quinone oxidoreductase‐1‐mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO‐induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases.     

Alzheimer's disease: synapses gone cold

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses.     

Temporal relationship of autophagy and apoptosis in neurons challenged by low molecular weight β‐amyloid peptide

Alzheimer's disease (AD) is an aging‐related progressive neurodegenerative disorder. Previous studies suggested that various soluble Aβ species are neurotoxic and able to activate apoptosis and autophagy, the type I and type II programmed cell death, respectively. However, the sequential and functional relationships between these two cellular events remain elusive. Here we report that low molecular weight Aβ triggered cleavage of caspase 3 and poly (ADP‐ribose) polymerase to cause neuronal apoptosis in rat cortical neurons. On the other hand, Aβ activated autophagy by inducing autophagic vesicle formation and autophagy related gene 12 (ATG12), and up‐regulated the lysoso‐mal machinery for the degradation of autophagosomes. Moreover, we demonstrated that activation of autophagy by Aβ preceded that of apoptosis, with death associated protein kinase phosphorylation as the potential molecular link. More importantly, under Aβ toxicity, neurons exhibiting high level of autophagosome formation were absent of apoptotic features, and inhibition of autophagy by 3‐methylade‐nine advanced neuronal apoptosis, suggesting that autophagy can protect neurons from Aβ‐induced apoptosis.     

Role of hippocalcin in mediating Aβ toxicity

Alzheimer's disease (AD) is the most common cause of dementia, and amyloid-β (Aβ) plaques and tau-containing tangles are its histopathological hallmark lesions. These do not occur at random; rather, the neurodegenerative process is stereotyped in that it is initiated in the entorhinal cortex and hippocampal formation. Interestingly, it is the latter brain area where the calcium-sensing enzyme hippocalcin is highly expressed. Because calcium deregulation is a well-established pathomechanism in AD, we aimed to address the putative role of hippocalcin in human AD brain and transgenic mouse models. We found that hippocalcin levels are increased in human AD brain and in Aβ plaque-forming APP23 transgenic mice compared to controls. To determine the role of hippocalcin in Aβ toxicity, we treated primary cultures derived from hippocalcin knockout (HC KO) mice with Aβ and found them to be more susceptible to Aβ toxicity than controls. Likewise, treatment with either thapsigargin or ionomycin, both known to deregulate intracellular calcium levels, caused an increased toxicity in hippocampal neurons from HC KO mice compared to wild-type. We found further that mitochondrial complex I activity increased from 3 to 6months in hippocampal mitochondria from wild-type and HC KO mice, but that the latter exhibited a significantly stronger aging phenotype than wild-type. Aβ treatment induced significant toxicity on hippocampal mitochondria from HC KO mice already at 3months of age, while wild-type mitochondria were spared. Our data suggest that hippocalcin has a neuroprotective role in AD, presenting it as a putative biomarker.     

Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models

Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-β (Aβ) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Aβ clearance In Aβ-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aβ only. Immunofluorescence revealed that MSC coculture in Aβ-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in Aβ-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Aβ-treated neuronal cells. Furthermore, MSC coculture markedly increased Aβ immunoreactivity colocalized within lysosomes and decreased intracellular Aβ levels compared with Aβ-treated cells. In Aβ-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of Aβ in the hippocampus, which was elevated in Aβ-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of Aβ in AD models, which may lead to increased neuronal survival against Aβ toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment.