Synergy between amyloid-β and tau in Alzheimer's disease

Abstract

Patients with Alzheimer's disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this 'triggering' function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ-tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.

Fig. 1 |. Aβ plaques accelerate tau spreading and cognitive decline in human AD.

Top: tau tangles (red) in the absence of concurrent cortical plaques are present in brain stem nuclei (for example, locus coeruleus) and the parahippocampal gyrus, which includes the eC, of many cognitively normal aged individuals (i.e., those with primary age-related tauopathy). In AD, the presence of cortical plaques (blue) correlates with neuronal tau propagation from the parahippocampal gyrus into neocortical areas, including medial parietal and medial prefrontal cortex^,. Bottom: human AD cases with plaques and tangles show a dramatically enhanced formation and propagation of bioactive, HMW forms of tau (right) relative to human cases with tangles alone (left).

Fig. 2 |. The interaction between Aβ and tau enhances neural circuit impairment.

Compared to the healthy brain (left), the cellular microenvironment adjacent to plaques (middle) is characterized by hyperactive neurons, microglia activation and spine loss (inset). the impairments are largely reversible following suppression of Aβ or endogenous tau. In vivo multiphoton imaging has revealed that the combined presence of Aβ and tau pathology in the neocortex (right) is associated with suppressed neuronal activity, as well as with enhanced microglia activation and spine loss^,. Suppression of Aβ or tau pathology alone is not effective in rescuing these functional impairments.

Fig. 3 |. Microglia may be critical intermediaries of Aβ–tau synergy.

Depicted are mechanisms by which microglia might contribute to enhanced bioactivity and spreading of tau in the presence of Aβ. Soluble Aβ and other factors, such as release of cytokines by senescent oligodendrocytes near plaques, can activate microglia. Activated microglia may take up tau, process it and release it in a more bioactive form. Neurons may take up released tau (possibly through an interaction with LRP1) and, in turn, release tau into the neuropil in an activity-dependent manner. Neuronal activity is enhanced by multiple mechanisms, including Aβ-mediated block of glutamate reuptake, impaired synaptic inhibition or blood-brain barrier (BBB) breakdown resulting in extravasation of neurotoxic products (for example, albumin, illustrated) and activation of astrocytic tGF-β signaling^,. Additional mechanisms by which microglia might contribute to tau seeding and propagation include the release of cytokines, chemokines and nitric oxide that enhance tau phosphorylation and perhaps direct transfer through microglia–neuron somatic junctions. Note that Aβ can also directly seed tau^,.

Fig. 4 |. Aβ and tau pathways may converge at the level of gene expression.

a, transcriptional dysregulation in crossed APPxtau models (green trace) exceeds that observed in APP (moderate gene changes, red trace) or tau (mild gene changes, blue trace) mice and outstrips that which would be expected from the combined effect of APP and tau (black dashed trace), suggesting Aβ–tau synergy at the level of gene expression. b, While gene upregulation in APPxtau models is concordant with that in either APP or tau mice, APPxtau models exhibit increased downregulation of genes compared to APP or tau models alone (black arrow), indicating an interaction between Aβ and tau in downregulating gene expression. c, Aβ-mediated glutamate-reuptake blockade results in increased action potential firing, which is associated with an influx of Ca²⁺ via L-type voltage gated Ca²⁺ channels (L-VGCC). Other sources of Ca²⁺ influx are Ca²⁺ permeable AMPA and NMDA receptors and Ca²⁺ release from internal stores (for example, endoplasmic reticulum, eR). Ca²⁺ elevations stimulate a signaling cascade, which includes the activation of the Ras-mitogen-associated protein kinase (MAPK), calmodulin-dependent protein kinases (CaMK) and calcineurin-mediated signaling pathways that have multiple effects, ranging from post-translational modifications of proteins (for example, tau) and alterations in cell surface trafficking of neurotransmitter receptors, to the initiation and modulation of transcriptional cascades. tau itself modulates transcriptional activity via multiple mechanisms, including impairment of nucleocytoplasmic transport and dysregulation of transposable elements^,. In addition, tau acts as a critical intermediate of Aβ-induced overexcitation by Fyn-dependent stabilization of NMDA receptors, and Fyn activation can independently promote the local translation and phosphorylation of tau. Aβ-mediated NMDA receptor overactivity, as well as stimulation of α2_a-receptors, leads to activation of GSK3-β (ref. ).