The intersection of amyloid β and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer's disease

Abstract

The synaptic connections that form between neurons during development remain plastic and able to adapt throughout the lifespan, enabling learning and memory. However, during aging and in particular in neurodegenerative diseases, synapses become dysfunctional and degenerate, contributing to dementia. In the case of Alzheimer's disease (AD), synapse loss is the strongest pathological correlate of cognitive decline, indicating that synaptic degeneration plays a central role in dementia. Over the past decade, strong evidence has emerged that oligomeric forms of amyloid beta, the protein that accumulates in senile plaques in the AD brain, contribute to degeneration of synaptic structure and function. More recent data indicate that pathological forms of tau protein, which accumulate in neurofibrillary tangles in the AD brain, also cause synaptic dysfunction and loss. In this review, we will present the case that soluble forms of both amyloid beta and tau protein act at the synapse to cause neural network dysfunction, and further that these two pathological proteins may act in concert to cause synaptic pathology. These data may have wide-ranging implications for the targeting of soluble pathological proteins in neurodegenerative diseases to prevent or reverse cognitive decline.

Keywords: Alzheimer; Amyloid beta; Synapse; Tau.

Figure 1

Alzheimer’s disease pathology. AD patient brains are characterized by gross atrophy of the hippocampus (arrow in A) and cortical thinning (arrowhead in A). Microscopically, the disease is defined by the presence of amyloid plaques (arrow in B) and neurofibrillary tangles (arrowhead in B). Plaques and tangles are both labeled by histological amyloid binding dyes such as thioflavin S shown here in panel B. Scale bars 1cm in A, 20 μm in B.

Figure 2

Model of synaptic effects of soluble tau in the rTg4510 model of tauopathy. In early tauopathy, dendritic architecture is preserved (1). Pathological soluble tau impairs microtubule-dependent transport in axons, which begin to die back distally (2), and in dendrites, where HCN channels subsequently insert into proximal dendritic and/or somatic membranes (3). The mislocalization and high density of HCN leads to an increased amplitude depolarizing sag potential at the soma (4), which contributes to significant depolarization of the resting membrane potential and associated increased action potential firing rates (5). Impaired trafficking to presynaptic sites may lead to a reduction and/or perturbation(s) in presynaptic vesicles (6a), whereas mislocalization of pathological soluble tau to spines (6b) and global disturbances in postsynaptic targeting, anchoring and/or turnover of glutamate receptors leads to a reduced density of postsynaptic AMPA receptors (6c). Excitatory synaptic transmission is disrupted, resulting in a higher proportion of low-amplitude sEPSCs (6d). In advanced tauopathy, some neurons possess intact apical dendritic tufts (7) due to distinctive initiation and progression of tau pathology, and/or patterns of deafferentation. The apical dendritic tuft is severely atrophic or is completely lost in many neurons; trans-synaptic transmission of tau pathology may contribute to this regressive process (8). Since approximately half of frontal cortical pyramidal neurons are lost, in part due to death cascades initiated by excitotoxicity (9), and remaining axons continue to regress (10), surviving neurons are deafferented. Spines density is decreased due to a specific reduction in mushroom spines and compensatory sprouting of filopodia and axonal boutons results in the formation new, albeit smaller excitatory synapses (11); these small synapses may account for the higher proportion of low-amplitude sEPSCs exhibited by some neurons (12). Many neurons with intact apical tufts demonstrate proliferative sprouting of oblique dendrites of the apical trunk (13) and may have increased numbers of shaft synapses (dashed box); these changes are consistent with an increased mean amplitude and proportion of high-amplitude sEPSCs (14). Compensatory responses (e.g. 11 and 13), in addition to further increased action potential firing rates, allow for relatively stable network function and preservation of some frontal lobe function (15).