The intersection of amyloid beta and tau at synapses in Alzheimer's disease - PubMed (original) (raw)

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The intersection of amyloid beta and tau at synapses in Alzheimer's disease

Tara L Spires-Jones et al. Neuron. 2014.

Abstract

The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer's disease (AD). We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of transsynaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse.

Copyright © 2014 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Neuropathology of AD

AD brains are characterized by striking atrophy compared to control brains (A). Particularly evident is shrinkage of the cortical mantle and the hippocampus (asterisk shows hippocampal atrophy). Microscopically, AD is defined by deposition of Aβ in senile plaques (arrowheads) and tau in neurofibrillary tangles (arrows). In this micrograph, the fibrillar deposits (both plaques and tangles) are stained green with thioflavine S. Aβ is also immunostained with antibody AW7 (courtesy Dominic Walsh), illustrating the halo of soluble Aβ around fibrillar plaque cores and the heterogeneous nature of plaques. Scale bars represent 1 cm (A) and 20 μm (B).

Figure 2

Figure 2. Structural changes in AD brain

The neural circuitry involved in memory including the entorhinal cortex-hippocampal circuitry (A) are severely affected by AD pathology including the deposition of plaques (blue) and tangles (green) and dramatic neuronal and synapse loss. Along with the dramatic neuronal loss, there are structural changes to remaining neurons in the AD brain that are thought to contribute to neural circuit disruption and cognitive impairments (B), including damage to neurites in the halo of soluble amyloid beta surrounding plaques, tau aggregation in cell bodies and neurites, and synapse loss associated with oligomeric Aβ around plaques. Panel A modified from (Gomez-Isla et al., 2008).

Figure 3

Figure 3. Dendritic spine loss in AD mouse models

Mouse models that exhibit plaque formation or tangle formation exhibit dendritic spine loss. Crossing APP/PS1 mice (A) and rTg4510 mice (B) with YFP overexpressing lines allowed quantification of dendritic spine density on cortical pyramidal neurons (layer II/III). Dense plaques are stained with thioflavine S in (A) and neurofibrillary tangles are stained with PHF1 antibody in B, while neurons in both panels are filled with YFP due to transgenic overexpression. Similar results are found when fluorescent markers are introduced via viral infection of neurons or direct injection of fluorophores. In plaque bearing mice, dendritic spine loss is most pronounced within 50 μm of plaques, whereas in tangle bearing mice, the presence of a tangle does not affect dendritic spine density (C). Data in C adapted from (Kopeikina et al., 2012b; Kopeikina et al., 2013; Rocher et al., 2010; Rozkalne et al., 2011; Spires et al., 2005). Scale bars represent 20 μm (A) and 50 μm (B).

Figure 4

Figure 4

Array tomography reveals colocalization of oligomeric Aβ with synapses in human brain. The array tomography technique overcomes the axial resolution of light microscopy by physically sectioning resin embedded brain tissue into ribbons of ultrathin (70nm) serial sections which are stained with immunofluorescence, imaged with a fluorescent microscope at the same place along the ribbon (red dots) and a three dimensional dataset acquired of multiple markers at synapses (A, D). Using human AD brain tissue (B–C), we observed oligomeric Aβ stained with NAB61 (red) present at a subset of synapses as can be seen in the inset in panel B (presynaptic terminals stained here with synapsin I, green). We also observe a reduction in synapse density in the halo of oligomeric Aβ surrounding the Thioflavin S (ThioS) positive dense cores of plaques (arrows). Scale bars represent 5 μm (B, C) and 1 μm (inset in B). Panel D is a reconstruction of a 36 μm × 33 μm × 1.2 μm volume (images from 17 serial sections). Panel A adapted from Micheva and Smith 2007.

Figure 5

Figure 5. Pathways involved in normal synaptic plasticity and how they may be affected in AD

Under normal conditions, LTP promotes recruitment of neurotransmitter receptors to active synapses and causes synapse potentiation, stabilization, and growth. LTD conversely results in synapse depotentiation and spine collapse. Both of these processes are affected in animal models of AD with oligomeric Aβ clearly affecting the calcium and calcineurin pathways involved in these phenomena. Tau overexpression has been observed to affect synaptic function in transgenic models and to be necessary for oligomeric Aβ mediated synapse dysfunction, but the mechanisms by which pathological forms of tau affect synaptic plasticity are less well understood. It is possible that hyperphosphorylation affects microtubule stability and the transport of mitochondria to synapses which could affect synaptic function. The cleavage of tau by caspase 3 has also been observed which could be tied to the non-apoptotic role of caspase 3 in LTD and spine collapse.

Figure 6

Figure 6. Synaptic effects of Aβ and tau

Many studies implicate oligomeric Aβ in synapse dysfunction and loss in models of AD. Aβ may be specifically trafficked to the synapse by apoE4, where it binds to postsynaptic receptors, causes an increase in calcium concentration, calcineurin activation, caspase 3 activation, and downstream internalization of synaptic receptors. Tau has also been implicated in synapse dysfunction downstream of Aβ, and pathological forms of tau (pTau) are transferred through synaptic circuits, although which forms of tau are transported and how they are transported remains to be determined. Figure courtesy A Hermann.

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