The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease

“…Both APP and tau are regulated by REST or SUZ12, and this may explain why the increases in levels of Aβ production markers and tau occur in tandem [ 6 ]. The increased concentration of neuronal plasticity proteins might reflect a compensatory mechanism triggered by tau-induced synaptic dysfunction such as impairment of presynaptic vesicle release, trafficking of glutamatergic receptors, and maturation of dendritic spines [ 65 ]. AD neuropathological studies suggested that such a plasticity response is likely pathological and results in aberrant synaptic sprouting (both at axons and at dendrites), disorganised capillairies and an abnormal cortical myelin architecture [ 51 , 52 , 66 ].…”

rTg(TauP301L)4510 mice exhibit increased VGLUT1 in hippocampal presynaptic glutamatergic vesicles and increased extracellular glutamate release

“…Therefore, our approach provides the advantage of measuring tau-mediated presynaptic vesicle release changes during their development, and in the presence of their appropriate astrocytic growth factors. Our observation of VGLUT1 and our isolation of presynaptic transmission from post-synaptic signaling allows for a direct measurement of the contribution of VGLUT1 in presynaptic transmission in tauopathy models. Previous age-dependent in vivo mouse model studies have been able to correlate changes in VGLUT1 expression levels and their effect on calcium (Wu et al, 2021) or glutamate (Hunsberger et al, 2014, 2015), but these studies could not directly measure if VGLUT1 levels mediated increased extracellular glutamate; this is particularly important because changes in VGLUT1 levels have been shown to directly affect presynaptic release probability (Wilson et al, 2005, p. 1). Direct measurements of VGLUT1 levels on synaptic transmission using in vitro cell culture methods were inconsistent with in vivo results (Siano et al, 2019), possibly due to the limitations of the cell culture approach used, as outlined above.…”

“…We finally put our results of increased extracellular glutamate in context with the established observed tau-mediated decrease in synaptic transmission. Multiple forms of hyperphosphorylated tau have been shown to reduce synaptic transmission by reducing presynaptic vesicle recycling via binding to single synaptic vesicles and reducing vesicle mobility (McInnes et al, 2018; Wu et al, 2021; Zhou et al, 2017). However, this leads to two competing mechanisms to the amount of extracellular glutamate released.…”

“…Pathological hyperphosphorylation and aggregation of tau is a hallmark of neurodegenerative conditions known as tauopathies, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Pick’s disease, and Frontotemporal dementia with Parkinsonson-17 (FTDP-17). While much of the work has focused on the role of pathological tau in disrupting postsynaptic signaling, there is growing interest in the role that pathological tau plays in presynaptic dysfunction (see (Wu et al, 2021) for review). Using the rTg(TauP301L)4510 mouse model (hereafter called tau P301L pos), we have previously demonstrated in vivo that P301L tau expression increases glutamate release in the hippocampus, which correlated with memory deficits, at a time when tau pathology was subtle and before readily detectable neuron loss (Hunsberger et al, 2014).…”

Connecting the Dots Between Hypercholesterolemia and Alzheimer’s Disease: A Potential Mechanism Based on 27-Hydroxycholesterol

“…Hyperphosphorylation may disengage tau from microtubules, and tau tends to misfold and aggregate to form NFT, which eventually impairs neuronal function. In addition, pathological tau induces synaptic dysfunction, which is another early pathological manifestation of AD ( Wu et al, 2021 ). Researchers found a significant association between hypercholesterolemia and all AD neuropathological outcomes, including NFT, by analyzing neuropathological and clinical data from subjects in the National Alzheimer’s Disease Coordinating Center (NACC) ( Xu et al, 2020 ).…”