. Paroxysmal slow cortical activity in Alzheimer's disease and epilepsy is associated with blood-brain barrier dysfunction. Sci Transl Med. 2019 Dec 4;11(521) PubMed.

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  1. These papers by Senatorov et al. and Milikovsky et al. demonstrate that BBB dysfunction initiates neuronal dysfunction, supporting the growing body of evidence that BBB breakdown contributes to synaptic dysfunction, neurodegeneration, and cognitive impairment, as we have shown in humans (Montagne et al., 2015; Nation et al., 2019) and animal models including pericyte-deficient (Bell et al., 2010; Montagne et al., 2018), pericyte-ablation (Nikolakopoulou et al., 2019), apolipoprotein E4 (Bell et al., 2012), or Glut1 endothelial-specific BBB knockout (Winkler et al., 2015) mice, to name a few.

    A common denominator in these studies, including these two new studies, is that dysfunctional BBB leaks toxic blood-derived products into the brain, such as fibrinogen, thrombin, plasminogen, iron-containing proteins, albumin, etc., which upset normal neuronal function, eventually causing neuronal and synaptic loss and/or cognitive decline in case of Alzheimer’s’ disease.

    Senatorov et al. show mechanistically that entry of albumin across the disrupted BBB activates TGFβ signaling pathways in astrocytes. In the aging mouse and human hippocampus, this in turn initiates neuronal dysfunction, which is reversible by genetic or pharmacological inhibition of the TGFβ pathway in the presence of an open BBB. Interestingly, we have shown that genetic or pharmacological blockade of pathways underlying BBB breakdown can also effectively reverse neuronal and synaptic changes (Bell et al., 2012Winkler et al, 2015). 

    Additionally, Milikovsky et al. link BBB breakdown to cortical epilepsy in Alzheimer’s disease patients and animal models. Both studies point to BBB as a promising new target to control cognitive impairment, which is likely an important new frontier for research into Alzheimer’s disease and related neurodegenerative disorders.

    References:

    . Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21;85(2):296-302. PubMed.

    . Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019 Feb;25(2):270-276. Epub 2019 Jan 14 PubMed.

    . Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010 Nov 4;68(3):409-27. PubMed.

    . Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med. 2018 Mar;24(3):326-337. Epub 2018 Feb 5 PubMed.

    . Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci. 2019 Jul;22(7):1089-1098. Epub 2019 Jun 24 PubMed.

    . Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed.

    . GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci. 2015 Apr;18(4):521-30. Epub 2015 Mar 2 PubMed.

    View all comments by Berislav Zlokovic
  2. What is new?
    The link between astrocytes and BBB dysfunction in aging is new and expands our understanding of the cellular bases of the pathogenic impact of the BBB on brain function and of the signaling mechanisms involved (TGFβ-SMAD etc.).

    I find it of interest that the data points to the involvement of the matrix, since also in CADASIL, a condition associated with profound microvascular alterations and dementia, matrix proteins have been shown to play a role (Capone et al., 2016; Capone et al., 2016). 

    As the authors point out, albumin is unlikely to be the sole factor involved and other circulating agents, particularly fibrinogen, have been shown to mediate brain dysfunction and damage upon BBB opening. In addition, innate immune cells can also enter the brain and they exhibit epileptogenic potential (Maroso et al., 2010). 

    Overall, this study contributes to expand our understanding of how BBB dysfunction leads to neuronal dysfunction by highlighting the role of astrocytes and albumin-induced TGFβ signaling. Mechanistically, the vascular bases of the BBB dysfunction (endothelium, etc.), as well as the link between TGFβ signaling and network activity leading to paroxysmal slow waves, remain to be elucidated. Since epileptic activity opens the BBB, it would also be of interest to assess if the seizures, once triggered, sustain or aggravate the BBB dysfunction creating a vicious circle that may exacerbate dysfunction and damage.

    Seizures and AD
    The second paper extends the findings of the first paper to AD patients and AD animal models, focusing on the role of the BBB dysfunction in the paroxysmal activity known to occur in AD.

    The paroxysmal slow-wave “signature” observed in patients and in models is of interest, but further studies are needed to clarify if it can be linked exclusively to the BBB alteration: The effects of Aβ, tau, α-synuclein, TDP43, etc., on network activity cannot be ignored.

    The EEG findings are impressive, but validation in large patient cohorts is needed. Furthermore, considering the multiplicity of brain pathologies underlying clinically diagnosed AD, correlation with postmortem neuropathologies (Aβ, tau, Lewy bodies, vascular damage, TDP43, etc.) would be revealing and could have potential diagnostic relevance by linking the paroxysmal activity to a specific pathology.

    What opens the BBB in the first place in aging and AD remains to be established. Could the seizure activity caused by BBB-independent factors be the initial trigger? Previous studies indicate Aβ- and tau-independent effects on the BBB in AD (Nation et al., 2019), but, again, the initial trigger remains unknown.

    References:

    . Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice. Ann Neurol. 2016 Mar;79(3):387-403. Epub 2016 Feb 10 PubMed.

    . Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. Elife. 2016 Aug 1;5 PubMed.

    . Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010 Apr;16(4):413-9. Epub 2010 Mar 28 PubMed.

    . Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019 Feb;25(2):270-276. Epub 2019 Jan 14 PubMed.

    View all comments by Costantino Iadecola
  3. Blood-brain barrier (BBB) dysfunction is increasingly emerging as an early and important mechanism that might underpin some of the cognitive changes seen as part of the aging process and in the development of neurodegenerative diseases, including Alzheimer’s. The mechanisms underlying these associations and their potential for drug modification are less clear.

    In a series of mouse and human experiments Senatorov et al. show that BBB dysfunction occurs with aging and leads to hyperactivation of TGFβ signaling in astrocytes, which in turn leads to neuronal network dysfunction, especially in the hippocampus. Importantly, in mice whose brains were infused with albumin to mimic BBB dysfunction, this could be modified by intraperitoneal infusions of a small-molecule TGFβR1 kinase inhibitor (IPW). In a separate but related study, Milikovsky et al. show a link between electrographic abnormalities—paroxysmal slow-wave events (PSWE)—detected using scalp EEG, and cognitive impairment. They show that PSWEs are seen in a number of human and mouse models of BBB dysfunction, and that PSWEs can be induced by exposing mouse brain to albumin.

    Together, these elegant studies provide more evidence for a connection between BBB impairment and neural dysfunction. They suggest that this interplay may be mediated by specific astrocyctic pathways, leading to electrographic dysfunction that can be quantified using scalp EEG, and importantly propose that this pathological pathway may be a tractable therapeutic target.

    Further studies are required to establish how well infusion of albumin into the central nervous system accurately mimics the presumably chronic effects of BBB breakdown in aging, the extent to which these mechanisms contribute to the cognitive changes seen in aging and neurodegenerative disease in humans, and whether strategies to block astrocytic TGFβ signaling (e.g. using IPW or losartan) are feasible, safe, and therapeutically useful for patients.

    View all comments by Jonathan Schott
  4. Milikovsky et al. devised a clever method to quantify discrete episodes of cortical slowing, termed paroxysmal slow-wave events (PSWEs), in AD and determined that these events had unique associations with blood-brain barrier dysfunction and degree of cognitive decline.

    Together, the papers provide a biologically plausible and intriguing mechanism by which a leaky blood-brain barrier could contribute to network hyperexcitability in aging and AD, as well as evidence that PSWEs correlate with signs of network hyperexcitability and cognitive decline. With the wide variability in PSWEs observed in AD, it will be interesting to see if this measure can gauge the degree of network hyperexcitability in individual cases of MCI and AD and help guide therapy. These studies also raise the level of interest in losartan and therapies targeting the TGFβ receptor for clinical trials in AD.

    A major category of genetic risk for AD involves the immune response, but how this might relate to network activity is poorly understood. These articles identify immune factor signaling that influences network activity and cognitive function in models of AD.

    View all comments by Keith Vossel
  5. This interesting study draws an important causal link between dysregulated innate immune signaling due to blood-brain-barrier breakdown and neural dysfunction in aging, which has important implications for age-related neurodegenerative diseases including AD. More specifically, the authors show that blood-brain-barrier dysfunction induces hyperactivation of TGF-β signaling. This, in turn, leads to an aged brain phenotype that includes aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment.

    It is becoming more appreciated that Alzheimer’s disease critically involves dysregulated innate immunity and chronic, low-level neuroinflammation that fails to support amyloid clearance. While considerable effort has been directed toward pro-inflammatory mechanisms of aging and AD, precious little attention has been given to understanding the impact of immune suppressive signals like TGF-β that become overly active in the AD brain and suppress beneficial innate immune responses. This study provides more clues as to the source and impact of hyperactive anti-inflammatory signals like TGF-β in the aging brain and thus points to this enigmatic cytokine as a promising therapeutic target to rebalance innate immunity and reverse neural dysfunction in aging and in AD. However, the importance of context needs to be stressed: TGF-β signaling inhibitors may be either beneficial or deleterious depending on which cells are targeted.

    View all comments by Anakha Ajayan
  6. These two interesting papers highlight the intimate interactions between vascular, astrocyte, and neuronal health. The focus on blood-brain barrier (BBB) dysfunction indicates what may be a common and early driver in pathology in AD, and very possibly other neurodegenerative/neurodevelopmental diseases.

    The reported early BBB breakdown in both studies caused an influx in serum components, most notably albumin, that was shown to bind to TGFβ receptors of astrocytes. While Tgfbr1 has been shown to only be lowly expressed in astrocytes during normal physiological conditions (see Zhang et al., 2104; 2016; Saunders et al., 2018), it remains to be seen if expression increases with aging in particular brain regions, or if genetic susceptibility in patients is likely to drive increased expression of the receptor. An alternative hypothesis is that the small number of astrocytes that do express the receptor are located close to the vasculature—making them particularly primed to mounting the TGFβ response. Either way, these two studies pave the way for continued investigation into the specific mechanism and timing associated with this disease-causing/progressing phenomenon.

    It will be interesting to know going forward if this is an effect due only to BBB breakdown, or if altered plexus transport dynamics could result in a similar seizure-inducing phenotype. There is considerable evidence for active plasma protein transport across the choroid plexus during early brain development. This transport is integral for setting up osmotic pressure gradients required for normal brain growth, see Davson, 1967; Adinolfi et al., 1976; Knott et al., 1997. Would a reversion to this developmental protein transport drive seizures in patients with intact BBB? An enticing possibility.

    References:

    . Permeability of the blood-cerebrospinal fluid barrier to plasma proteins during foetal and perinatal life. Nature. 1976 Jan 15;259(5539):140-1. PubMed.

    . Physiology of the cerebrospinal fluid. Little Brown and Company, London. 1967

    . Albumin transfer across the choroid plexus of South American opossum (Monodelphis domestica). J Physiol. 1997 Feb 15;499 ( Pt 1):179-94. PubMed.

    . Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain. Cell. 2018 Aug 9;174(4):1015-1030.e16. PubMed.

    . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014 Sep 3;34(36):11929-47. PubMed.

    . Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron. 2016 Jan 6;89(1):37-53. Epub 2015 Dec 10 PubMed.

    View all comments by Shane Liddelow
  7. We would like to contribute to the discussion about blood-borne factors entering the brain, with the two STM studies reporting that age-related impairments in the BBB allow for an influx of albumin into the brain, activating TGFβ receptors, overexciting neuronal networks, and impairing cognition.

    We are working in the space of developing therapeutic ultrasound-mediated BBB opening as a treatment option for Alzheimer's disease. The BBB opening which is being achieved involves the uptake of albumin by the brain, as evidenced in experiments where Evans Blue is intravenously injected to visualize BBB opening. Incidentally, Evans Blue uses albumin as a carrier to enter the brain. In other words, when we use therapeutic ultrasound in combination with intravenously injected microbubbles into the brain, albumin enters the brain.

    We have repeatedly treated amyloid-depositing APP23 mice with ultrasound, opening the BBB four to seven times weekly (Leinenga and Götz, 2015: Leinenga and Götz, 2018: Leinenga et al., 2019), and we have also treated tau transgenic K3 and pR5 mice repeatedly (up to 14 times weekly, Nisbet et al., 2017; Janowics et al., 2019; Pandit et al., 2019), as well as sheep (Pelekanos et al., 2018).  In no instance did we observe impaired cognition. Much in contrast, we observed an improvement or even restoration of memory to wild-type levels.

    We have also performed a large set of safety studies in wild-type mice of middle to high age, with no indication of any overt damage (Hatch et al., 2016: Blackmore et al., 2018). 

    We did not observe increased spontaneous seizures in any of our studies, but have not addressed this systematically, knowing from our own work that APP23 mice are prone to spontaneous seizures and are more sensitive to PTZ-induced seizures (Ittner et al., 2010). 

    In our view, more work needs to be invested into how the neurovascular unit differs between Alzheimer's disease and healthy control brains, how it changes with age, and also into how experimentally induced BBB opening differs from that which may occur in an aged diseased brain.

    References:

    . Multimodal analysis of aged wild-type mice exposed to repeated scanning ultrasound treatments demonstrates long-term safety. Theranostics. 2018;8(22):6233-6247. Epub 2018 Nov 29 PubMed.

    . Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions. Theranostics. 2018;8(9):2583-2602. Epub 2018 Apr 3 PubMed.

    . Scanning Ultrasound (SUS) Causes No Changes to Neuronal Excitability and Prevents Age-Related Reductions in Hippocampal CA1 Dendritic Structure in Wild-Type Mice. PLoS One. 2016;11(10):e0164278. Epub 2016 Oct 11 PubMed.

    . Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci Transl Med. 2015 Mar 11;7(278):278ra33. PubMed.

    . Safety and Efficacy of Scanning Ultrasound Treatment of Aged APP23 Mice. Front Neurosci. 2018;12:55. Epub 2018 Feb 7 PubMed.

    . Scanning ultrasound in the absence of blood-brain barrier opening is not sufficient to clear β-amyloid plaques in the APP23 mouse model of Alzheimer's disease. Brain Res Bull. 2019 Nov;153:8-14. Epub 2019 Aug 7 PubMed.

    . Ultrasound-mediated blood-brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody. Sci Rep. 2019 Jun 25;9(1):9255. PubMed.

    . Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017 Mar 4; PubMed.

    . Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions. Theranostics. 2019;9(13):3754-3767. Epub 2019 May 31 PubMed.

    . Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.

    View all comments by Jürgen Götz

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