Ablating Tau Reduces Hyperexcitability and Moderates Electroencephalographic Slowing in Transgenic Mice Expressing A53T Human α-Synuclein

Abstract

Abnormal intraneuronal accumulation of the presynaptic protein α-synuclein (α-syn) is implicated in the etiology of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Recent work revealed that mice expressing human α-syn with the alanine-53-threonine (A53T) mutation have a similar phenotype to the human condition, exhibiting long-term potentiation deficits, learning and memory deficits, and inhibitory hippocampal remodeling, all of which were reversed by genetic ablation of microtubule-associated protein tau. Significantly, memory deficits were associated with histological signs of network hyperactivity/seizures. Electrophysiological abnormalities are often seen in parkinsonian dementias. Baseline electroencephalogram (EEG) slowing is used as a supportive diagnostic feature in DLB and PDD, and patients with these diseases may exhibit indicators of broad network dysfunction such as sleep dysregulation, myoclonus, and seizures. Given the translational significance, we examined whether human A53T α-syn expressing mice exhibit endogenous-tau-dependent EEG abnormalities, as measured with epidural electrodes over the frontal and parietal cortices. Using template-based waveform sorting, we determined that A53T mice have significantly high numbers of epileptiform events as early as 3-4 months of age and throughout life, and this effect is markedly attenuated in the absence of tau. Epileptic myoclonus occurred in half of A53T mice and was markedly reduced by tau ablation. In spectral analysis, tau ablation partially reduced EEG slowing in 6-7 month transgenic mice. We found abnormal sleeping patterns in transgenic mice that were more pronounced in older groups, but did not find evidence that this was influenced by tau genotype. Together, these data support the notion that tau facilitates A53T α-syn-induced hyperexcitability that both precedes and coincides with associated synaptic, cognitive, and behavioral effects. Tau also contributes to some aspects of EEG slowing in A53T mice. Importantly, our work supports tau-based approaches as an effective early intervention in α-synucleinopathies to treat aberrant network activity.

Reduced Interaction of Aggregated α-Synuclein and VAMP2 by Environmental Enrichment Alleviates Hyperactivity and Anxiety in a Model of Parkinson’s Disease

“…However, the physiological roles of α-Syn in the non-motor symptoms of PD are yet to be fully elucidated. Consistent with the findings of a previous study [ 53 , 54 ], the present study showed that the mice did not show motor deficits in the grip strength test, hanging wire test, or cylinder test, but non-motor symptoms, such as anxiety and hyperactivity, were revealed in the mice, as shown by the open field test results in Figure 1 F,G.…”

Early Disruption of Cortical Sleep-Related Oscillations in a Mouse Model of Dementia With Lewy Bodies (DLB) Expressing Human Mutant (A30P) Alpha-Synuclein

“…Myoclonus can also be treated with levetiracetam (Caviness, 2014), thus it would be interesting to see if drugs aimed at reducing hyperexcitability could restore the changes in sleep-related oscillations we have observed as a result of the α-syn pathology in the A30P mouse model. Interestingly, epilepsy and myoclonus have recently been reported in A53T α-syn mice which was associated with reduced NREM sleep and more time spent in the awake state (Peters et al, 2020). Ours and other data, therefore, support the idea that early interventions aimed at improving sleep cycle regulation and sleep-related oscillations could be beneficial, not only in AD (Mander et al, 2016) and PD (Bohnen and Hu, 2019), but also in patients with DLB.…”

“…Using mice that over-express human wild-type α-syn to model DLB, a shift of power from higher alpha to lower theta frequencies was also found in awake mice (Morris et al, 2015), and during NREM and REM sleep (McDowell et al, 2014). Studies in transgenic α-syn mice which have also shown alterations in the sleep-wake cycle in awake-behaving animals (Rothman et al, 2013;McDowell et al, 2014;Peters et al, 2020). However, detailed studies of the SO and spindles in murine models of α-syn are currently lacking.…”

Emerging Electroencephalographic Biomarkers to Improve Preclinical to Clinical Translation in Alzheimer’s Disease

“…These events coincided with a leftward shift in baseline EEG power reflecting a greater proportion of low frequency activity ( Morris et al, 2015 ). When overexpression of a mutant transgene of α-synuclein (A53S) is combined in a mouse lacking endogenous tau, EEG-slowing induced by overexpression of α-synuclein is markedly attenuated, suggesting a clear link between these two proteins in seizure pathology witnessed in DLB ( Peters et al, 2020 ).…”