Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease.

Synapse number is the best indicator of cognitive impairment In Alzheimer's disease (AD), yet the respective contributions of Aß and tau, particularly human wild-type tau, to synapse loss remain undefined. Here, we sought to elucidate the Aß-dependent changes in wild-type human tau that trigger synapse loss and cognitive decline in AD by generating two novel transgenic mouse models. The first overexpresses floxed human APP with Swedish and London mutations under the thy1 promoter, and recapitulates important features of early AD, including accumulation of soluble Aß and oligomers, but no plaque formation. Transgene excision via Cre-recombinase reverses cognitive decline, even at 18-months of age. Secondly, we generated a human wild-type tau-overexpressing mouse. Crossing of the two animals accelerates cognitive impairment, causes enhanced accumulation and aggregation of tau, and results in reduction of dendritic spines compared to single transgenic hTau or hAPP mice. These results suggest that Aß-dependent acceleration of wild-type human tau pathology is a critical component of the lasting changes to dendritic spines and cognitive impairment found in AD.

Soluble aß promotes wild-type tau pathology in vivo.

Growing evidence suggests that soluble Aß species can drive Alzheimer disease (AD) pathogenesis by inducing a cascade of events including tau hyperphosphorylation, proteasome impairment, and synaptic dysfunction. However, these studies have relied largely on in vitro approaches to examine the role of soluble Aß in AD. In particular, it remains unknown whether soluble Aß oligomers can facilitate the development of human wild-type tau pathology in vivo. To address this question, we developed a novel transgenic model that expresses low levels of APP with the Arctic familial AD mutation to enhance soluble Aß oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of ß-site APP cleaving enzyme (BACE) in these ArcTau mice decreases soluble Aß oligomers, rescues cognition, and, more importantly, reduces tau accumulation and phosphorylation. Notably, BACE reduction decreases the postsynaptic mislocalization of tau in ArcTau mice and reduces the association between NMDA receptors and PSD-95. These studies provide critical in vivo evidence for a strong mechanistic link between soluble Aß, wild-type tau, and synaptic pathology.

Calpain inhibitor A-705253 mitigates Alzheimer's disease-like pathology and cognitive decline in aged 3xTgAD mice.

Calpains are cysteine proteinases that selectively cleave proteins in response to calcium signals. Exacerbated activation of calpain has been implicated as a major component in the signaling cascade that leads to ß-amyloid (Aß) production and tau hyperphosphorylation in Alzheimer's disease (AD). In this study, we analyzed the potential therapeutic efficacy of inhibiting the activation of calpain by a novel calpain inhibitor in aged 3xTgAD mice with well-established cognitive impairment, plaques, and tangles. The administration of a novel inhibitor of calpain, A-705253, attenuated cognitive impairment and synaptic dysfunction in a dose-dependent manner in 3xTgAD mice. Inhibition of calpain lowered Aß(40) and Aß(42) levels in both detergent-soluble and detergent-insoluble fractions and also reduced the total number and size of thioflavin S-positive fibrillar Aß deposits. Mechanistically, these effects were, in part, explained by a down-regulation of ß-secretase 1 (BACE1) and an up-regulation of ATP-binding cassette transporter A1 (ABCA1) expression, which, in turn, contributed to reduced production and increased clearance of Aß, respectively. Moreover, A-705253 decreased the activation of cyclin-dependent kinase 5 (CDK5) and thereby diminished the hyperphosphorylation of tau. Finally, blockage of calpain activation reduced the astrocytic and microglial responses associated with AD-like pathological characteristics in aged 3xTgAD mice. Our data provide relevant functional and molecular insights into the beneficial therapeutic effects of inhibiting calpain activation for the management of AD.

Elucidating the triggers, progression, and effects of Alzheimer's disease.

As the number of patients with Alzheimer's disease (AD) continues to rise, the need for efficacious therapeutics is becoming more and more urgent. Understanding the molecular relationship and interactions between Aß and tau and their contribution to cognitive decline remain one of the most fundamental and unresolved questions in the AD field. Likewise, elucidating the initial triggers of disease pathology, as well as the impact of various factors such as stress and inflammation on disease progression, are equally important to fully understand this devastating disorder. Here we discuss recent studies that have illuminated the importance of key facilitators of disease progression using the 3xTg-AD and CaM/Tet-DTA mouse models, and suggest viable targets for ameliorating both molecular pathology and cognitive decline.

ß-Amyloid impairs axonal BDNF retrograde trafficking.

The neurotrophin, brain-derived neurotrophic factor (BDNF), is essential for synaptic function, plasticity and neuronal survival. At the axon terminal, when BDNF binds to its receptor, tropomyosin-related kinase B (TrkB), the signal is propagated along the axon to the cell body, via retrograde transport, regulating gene expression and neuronal function. Alzheimer disease (AD) is characterized by early impairments in synaptic function that may result in part from neurotrophin signaling deficits. Growing evidence suggests that soluble ß-amyloid (Aß) assemblies cause synaptic dysfunction by disrupting both neurotransmitter and neurotrophin signaling. Utilizing a novel microfluidic culture chamber, we demonstrate a BDNF retrograde signaling deficit in AD transgenic mouse neurons (Tg2576) that can be reversed by γ-secretase inhibitors. Using BDNF-GFP, we show that BDNF-mediated TrkB retrograde trafficking is impaired in Tg2576 axons. Furthermore, Aß oligomers alone impair BDNF retrograde transport. Thus, Aß reduces BDNF signaling by impairing axonal transport and this may underlie the synaptic dysfunction observed in AD.