Summary While the microtubule-binding capacity of the protein tau has been known for many years, new functions of tau in signaling and cytoskeletal organization have recently emerged. In this review, we highlight these functions and the potential roles of tau in neurodegenerative disease. We also discuss the therapeutic potential of drugs targeting various aspects of tau biology.

The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites in wild-type mice. Wild-type and hAPP mice had similar modifications, supporting the hypothesis that neuronal dysfunction in hAPP mice is enabled by physiological forms of tau. Our findings provide clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.

The microtubule-associated protein tau is expressed throughout the nervous system, most highly in neurons but also in glial cells. Its functions in adult and aging mammals remain to be defined. Previous studies in mouse models found either protective or detrimental effects of genetic tau ablation. While tau ablation prevented synaptic, network and cognitive dysfunctions in several models of Alzheimer’s disease and made mice more resistant to epileptic seizures, a recent study described a parkinsonian phenotype in aging Tau knockout mice. Here we tested cognition and motor functions in Tau+/+, Tau+/− and Tau−/− mice around 1 and 2 years of age. Tau ablation did not impair cognition and caused only minor motor deficits that were much more subtle than those associated with the aging process. Tau ablation caused a mild increase in body weight, which correlated with and may have contributed to some of the motor deficits. However, tau ablation did not cause significant dopaminergic impairments, and dopamine treatment did not improve the motor deficits, suggesting that they do not reflect extrapyramidal dysfunction.

Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau +/+, Tau +/– and Tau –/– backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition.

ObjectiveDementia with Lewy bodies (DLB) is associated with the accumulation of wild‐type human α‐synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.MethodsTo determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity‐dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB.ResultsWe demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power.InterpretationWe conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

IMPORTANCELoss of smell is an early and common presentation of COVID-19 infection.Although it has been speculated that viral infection of olfactory neurons may be the culprit, it is unclear whether viral infection causes injuries in the olfactory bulb region.OBJECTIVE To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study. DESIGN, SETTING, AND PARTICIPANTSThis multicenter postmortem cohort study was conducted from April 7, 2020, to September 11, 2021. Deceased patients with COVID-19 and control individuals were included in the cohort. One infant with congenital anomalies was excluded. Olfactory bulb and tract tissue was collected from deceased patients with COVID-19 and appropriate controls. Histopathology, electron microscopy, droplet digital polymerase chain reaction, and immunofluorescence/immunohistochemistry studies were performed. Data analysis was conducted from February 7 to October 19, 2021. MAIN OUTCOMES AND MEASURES (1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue. RESULTS Olfactory tissue from 23 deceased patients with COVID-19 (median [IQR] age, 62 [49-69] years; 14 men [60.9%]) and 14 control individuals (median [IQR] age, 53.5 [33.25-65] years; 7 men [50%]) was included in the analysis. The mean (SD) axon pathology score (range, 1-3) was 1.921 (0.569) in patients with in controls (P < .001), whereas axon density was 2.973 (0.963) × 10 4 /mm 2 in patients with COVID-19 and 3.867 (0.670) × 10 4 /mm 2 in controls (P = .002). Concomitant endothelial injury of the microvasculature was also noted in olfactory tissue. The mean (SD) microvasculopathy score (range, 1-3) was 1.907 (0.490) in patients with COVID-19 and 1.405 (0.233) in control individuals (P < .001). Both the axon and microvascular pathology was worse in patients with COVID-19 with smell alterations than those with intact smell (mean [SD] axon pathology score, 2.260 [0.457] vs 1.63 [0.426]; P = .002; mean [SD] microvasculopathy score, 2.154 [0.528] vs 1.694 [0.329]; P = .02) but was not associated with clinical severity, timing of infection, or presence of virus.CONCLUSIONS AND RELEVANCE This study found that COVID-19 infection is associated with axon injuries and microvasculopathy in olfactory tissue. The striking axonal pathology in some cases indicates that olfactory dysfunction in COVID-19 infection may be severe and permanent.

Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4+ T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intracerebroventricular delivery of gut T lymphocytes from mice with NEC into Rag1−/− recipient mice lacking CD4+ T cells resulted in brain injury. Brain organoids derived from mice with or without NEC and from human neuronal progenitor cells revealed that IFN-γ release by CD4+ T lymphocytes induced microglial activation and myelin loss in the organoids. IFN-γ knockdown in CD4+ T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1−/− recipient mice. T cell receptor sequencing revealed that NEC mouse brain-derived T lymphocytes shared homology with gut T lymphocytes from NEC mice. Intraperitoneal injection of NEC gut-derived CD4+ T lymphocytes into naïve Rag1−/− recipient mice induced brain injury, suggesting that gut-derived T lymphocytes could mediate neuroinflammation in NEC. These findings indicate that NEC-associated brain injury may be induced by gut-derived IFN-γ–releasing CD4+ T cells, suggesting that early management of intestinal inflammation in children with NEC could improve neurological outcomes.

These observations indicate that, under these experimental conditions, AMPH-induced activation of the forebrain is dependent on actions of noradrenergic beta-receptors. Combined with previous observations, these observations support the hypothesis that AMPH-induced increases in arousal involve noradrenergic neurotransmission at beta-receptors.