Park L, Hochrainer K, Hattori Y, Ahn SJ, Anfray A, Wang G, Uekawa K, Seo J, Palfini V, Blanco I, Acosta D, Eliezer D, Zhou P, Anrather J, Iadecola C. Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration. Nat Neurosci. 2020 Sep;23(9):1079-1089. Epub 2020 Aug 10 PubMed.

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Comments

  1. In this elegant paper, the authors demonstrated for the first time that the P301L/S mutation in tau attenuated the activity-dependent increase in blood flow to the brain. It is widely believed that cerebrovascular dysfunction in Alzheimer’s disease (AD) probably arises from cerebral amyloid angiopathy, in which amyloid-β deposits in the walls of small to medium blood vessels trigger the pathological blockade of these vessels. The present study instead provides a very novel and highly significant mechanistic link between tau abnormalities and cerebrovascular impairments, challenging the prevalent view.

    One common mechanism for pathogenesis of neurodegenerative diseases involves the redistribution of the microtubule-associated protein tau from the axon into the somatodendritic compartment of neurons, followed by the mislocalization of tau into dendritic spines, resulting in postsynaptic functional deficits. The current study convincingly demonstrated that the disruption of the coupling between NMDA receptor and nitric oxide synthase by tau inhibited activity-triggered vasodilation. These results directly link postsynaptic activity to cerebrovascular dysfunction, providing a novel concept for how tau abnormalities can lead to some of the earliest pathophysiological changes during AD progression.

    Nevertheless, the manuscript has not yet resolved the role of wild-type tau in angiopathy. Most AD patients do not have genetic mutations in tau. It will be interesting to know how changes in the expression level and postsynaptic modifications of tau contribute to the cerebrovascular dysfunction. Here, only transgenic-negative mice were used as the wild-type control. Additional experiments using transgenic mice expressing wild-type human tau proteins at different levels will likely present a clearer picture.

    View all comments by Dezhi Liao

  2. Park et al. use a combination of imaging methods including ASL-MRI and two-photon microscopy, as well as electrophysiology and biochemistry to examine neurovascular coupling in two lines of human-tau-overexpressing mice. Critically, they show that blood vessels in young tau mice fail to dilate properly and blood flow does not increase in response to a whisker-stimulation task, despite similar extents of neuronal activation when compared with wild-type controls. We had previously reported that, surprisingly, aged tau-overexpressing mice had abnormal blood vessels, including reduced overall capillary diameter, occlusion by leukocytes, and increasing tortuosity, which suggests impaired blood flow could contribute to ongoing processes of neurodegeneration (Bennett et al., 2018). By visualizing related changes in much younger mice, these data indicate that such blood flow abnormalities precede neuronal loss and thus may play a causal role.

    This work is exciting, helping define a possible route of tau-mediated neurodegeneration and adding to a growing stack of evidence that tau and vasculature are intertwined. Disentangling this link could lead to new ideas in our understanding and treatment of Alzheimer’s disease: Are there specific pathologic soluble tau species that are responsible for disrupting neurovascular coupling and can they be targeted to improve disease outcome? Are there additional routes by which tau affects vasculature at different stages of the disease course? In following, are there points at which targeting tau may not provide the same benefits as seen when the authors suppressed tau expression early on in these mice? Importantly, is tau similarly affecting blood flow in human disease?

    Altered BOLD-fMRI signal in Alzheimer’s hints that this could be the case and in an excellent talk at the AD/PD meeting in April this year, Michael Ewers presented tau PET data indicating regions with tau accumulation are associated with reduced cerebral blood flow. I look forward to seeing this area of science continue to grow and eagerly anticipate work from neuroimaging groups using combined PET/MRI techniques to assess similar relationships between tau and vasculature in human disease.

    References:

    Bennett RE, Robbins AB, Hu M, Cao X, Betensky RA, Clark T, Das S, Hyman BT. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1289-E1298. Epub 2018 Jan 22 PubMed.

    View all comments by Rachel Bennett

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News

  1. With Tau in Synapses, NO Neurovascular Coupling

Mutations

  1. MAPT P301L