When too much tau invades dendrites, synaptic signaling goes haywire. Now, researchers led by Costantino Iadecola at Weill Cornell Medical College, New York, accuse this mislocalized tau of disrupting neurovascular coupling as well. In the August 10 Nature Neuroscience, they report that young mice overexpressing mutant human tau cannot amplify blood flow in their brains in response to neuronal activity. The defect was caused by soluble tau in the postsynapse. The protein displaced neuronal nitric oxide synthase, preventing synaptic activity from spurring nitric oxide production. Without NO, blood vessels did not expand. “This may be one of the earliest manifestations of tau pathology,” Iadecola told Alzforum. He believes this unresponsive vasculature could make it more difficult for the brain to clear toxic proteins, leading to further harmful effects.
- In mouse models of tauopathy, neurovascular coupling flags before tangles form.
- Soluble tau in the synapse displaces nitric oxide synthase.
- Without NO, blood vessels cannot dilate in response to neuronal activity.
“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,” Rachel Bennett at Massachusetts General Hospital, Boston, wrote to Alzforum (full comment below).
According to data from the Alzheimer’s Disease Neuroimaging Initiative, neurovascular dysfunction may be one of the earliest signs of AD, preceding even amyloid buildup (Jul 2016 news). Cardiovascular risk factors and amyloid burden together conspire to worsen tau pathology (Rabin et al., 2019). However, few studies have investigated the effects of tau pathology itself on the vasculature.
First author Laibaik Park addressed this by examining cerebral blood flow in two different tauopathy mouse models, PS19 and rTg4510. Both express mutant human tau—P301S and P301L, respectively—and develop tangles after four to six months. Memory problems and neuron loss follow. In the rTg4510 line, the tau transgene is under the control of a tetracycline response element, and can be shut off by feeding the mice doxycycline.
The researchers assessed cortical blood flow through a cranial window at 2 to 3 months of age, before tangles formed. Blood moved at normal volume, and increased in response to agonists that act on endothelial and smooth muscle cells. However, the animals’ vasculatures had a specific defect in neurovascular coupling. When the researchers tweaked the mouse’s whiskers, the surge in blood flow in the barrel cortex was only half that in control mice (see image above).
Though these young mice had no tangles, tau was abnormally phosphorylated at Ser202/Thr205, as seen by immunostaining with the AT8 antibody, and this p-tau had accumulated in dendrites. Dendritic tau has been associated with Aβ-mediated excitotoxicity and with reduced synaptic signaling (Jul 2010 conference news; Sep 2010 news; Jan 2011 news). To find out if abnormal tau was responsible for the defects in neurovascular coupling, the authors turned off transgene production in the rTg4510 mice by feeding them doxycycline.
When tau expression was suppressed starting at 3 months of age, neurovascular coupling was normal four months later, suggesting that removing dendritic tau reverses defects. These mice also maintained cortical thickness and memory comparable to controls at 7 months, in contrast to deficits seen in rTg4510 mice with constant transgene expression. Strengthening the idea that the defects in neurovascular coupling were caused by soluble tau, the authors were able to reproduce them by adding recombinant wild-type or mutant tau directly to the barrel cortices of wild-type mice.
Why didn’t blood vessels respond in the presence of tau? Normally, neuronal activity triggers neuronal nitric oxide synthase (nNOS), which is bound to NMDA receptors in the postsynapse through the adaptor protein PSD95 (Kornau et al., 1995; Brenman et al., 1996). Activation of nNOS produces NO, which dilates blood vessels. In the tauopathy mouse models, however, less than half the normal amount of nNOS was present at the synapse, as seen by co-immunoprecipitation with PSD95. In addition, neurons isolated from these mice did not produce NO in response to NMDA, confirming a defect.
To explore the mechanism, the researchers expressed mutant P301L tau together with PSD95 and nNOS in cultured HEK293T cells, then used co-immunoprecipitations to see if any bound together. Tau and nNOS bound to the same site on PSD95. The findings imply that excess tau in dendrites displaces nNOS, disrupting signaling.
“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,” Dezhi Liao at the University of Minnesota, Minneapolis, wrote to Alzforum (full comment below). He noted that the findings contrast with the prevailing belief that cerebral amyloid angiopathy is responsible for vascular problems in AD (Aug 2002 news). He suggested that future work might pin down which forms of tau are toxic by exploring the effects of physiological levels of wild-type and unphosphorylated human tau. All tau used in Iadecola’s experiments was phosphorylated at Ser202/Thr205.
What might loss of NO do to the brain? Iadecola noted that this signaling molecule does more than dilate blood vessels. It also stimulates neurogenesis in response to activity and it suppresses tau phosphorylation (Shen et al., 2019; Oct 2019 news). In addition, the NO-dependent change in blood vessel diameter has been linked to clearance of solutes such as Aβ from the brain (van Veluw et al., 2020). If tau interferes with NO production, that could lead to multiple defects that could worsen tau and even Aβ pathology, Iadecola suggested.
Park and colleagues are developing peptides that interfere with tau binding to PSD95 without harming nNOS binding. Once they have a good candidate, they will test it in mouse models to see if it preserves neurovascular coupling, Iadecola said. In theory, such a treatment could help people with AD, because Aβ causes tau to move into dendrites, as well as people with frontotemporal dementia, since tau mutations are common in that disorder.
Bennett noted that research presented at the virtual AD/PD conference in April suggests tau accumulation in human brain diminishes blood flow (see comment below). “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,” Bennett wrote. Intriguingly, some prior research has linked cerebrovascular disease to increased tangles and cognitive decline (May 2018 news).—Madolyn Bowman Rogers
- LOAD of Data Place Vascular Malfunction as Earliest Event in Alzheimer’s
- Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse
- The Plot Thickens: The Complicated Relationship of Tau and Aβ
- Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication
- Amyloid in Transgenic AβPP Mice Affects Blood Flow
- Not Just Blood Pressure—Dietary Salt Linked to Tau Phosphorylation
- Cerebrovascular Disease: Does Tau Mediate Cognitive Decline?
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- 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.