. Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes. Science. 2019 Jul 19;365(6450) Epub 2019 Jun 20 PubMed.


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  1. The story of the vascular effects of Aβ is evolving steadily, and the present paper, in conjunction with the paper of Cruz Hernández et al., 2019, represents the latest chapters.

    It has been known for a while that Aβ is a vasoconstrictor acting through free radicals derived from NADPH oxidase, and that counteracting these vascular effects rescues cognitive impairment in mouse models of Aβ accumulation, attesting to their pathogenic relevance (Park et al., 2005; Park et al., 2008). Subsequent studies identified the Aβ-binding scavenger receptor CD36 and NOX2 in perivascular macrophage associated with resistance arterioles as the source of the radicals and contributing to the neurovascular dysfunction (Park et al., 2011; Park et al., 2017). The ultimate effector of the dysfunction, downstream of radicals, was identified to be dysregulated opening of the TRPM2 channels and Ca2+ overload in cerebral endothelial cells (Park et al., 2014). 

    The present study extends these observations in several respects. First, it implicates vasoactivity of capillaries in the microvascular effects of Aβ. Second, it identifies capillary mural cells, such as pericytes, as critical for the capillary constriction. Third, it suggests that in these cells NOX4, rather than NOX2, is the source of the radicals involved in the capillary constriction. Fourth, and most importantly, it verifies some of these observations in freshly collected human brain samples. The importance of capillaries as a relevant microvascular site for the effects of Aβ on cerebral perfusion is also suggested by the Cruz Hernández study, demonstrating that transient occlusions of capillaries by circulating leukocytes (capillary stalling) contributes to the cerebral hypoperfusion associated with Aβ accumulation, and that counteracting the stalling rescues the reduction of cerebral blood flow and cognitive function in mice overexpressing APP (Cruz Hernández et al., 2019). 

    These observations, in concert with accumulating evidence of blood-brain barrier dysfunction in AD (Nation et al., 2019) and capillary transit time abnormality (Gutiérrez-Jiménez et al., 2018), point to an emerging role of cerebral capillaries in the vascular pathobiology of Aβ and reinforce the idea that Aβ acts at all levels of the cerebrovascular tree and on different cells to exert its deleterious effects on the brain circulation. Evidence demonstrating that rescuing the pericyte contribution to this process ameliorates cognitive function would be the next step in building the case that targeting pericytes and capillary vasoactivity is a viable strategy to counteract the neurovascular dysfunction induced by Aβ.


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    View all comments by Costantino Iadecola
  2. Vasoactive properties of peptides have been known for more than 20 years. For example, in the mid-1990s Aβ peptides were shown to induce vasoconstriction in the isolated rat aorta, which was ameliorated by superoxide dismutase 1 (SOD1) implicating involvement of reactive oxygen species (ROS) (Thomas et al., 1996). The follow-up studies in young Tg2576 mice overexpressing human APP (Swedish mutation) indicated that Aβ reduces cerebrovascular reactivity to endothelium-dependent vasodilators (for example, acetylcholine, bradykinin, or calcium ionophore A23187) and increases response to vasoconstrictors acting directly on vascular smooth muscle cells (VSMCs) (for example, the thromboxane A2 analogue U46619) (Zhang et al., 1997; Iadecola et al., 1999), that was associated with impaired neurovascular coupling (the dynamic functional change in cerebral blood flow that occurs in response to local neuronal activity) (Niwa et al., 2000). These abnormal vascular responses could again be rescued with SOD1, confirming involvement of ROS in vivo (Iadecola et al. 1999). Collectively, these pioneering studies suggest that accumulation of low levels of soluble Aβ (likely Aβ oligomeric species) before Aβ deposition leads to a global impairment of vascular responses. Moreover, in the brain endothelium Aβ-mediated oxidant stress led to proinflammatory changes in cerebral blood vessels and generation of endothelin 1 (ET1) through the receptor for advanced glycosylation end products (RAGE), which binds Aβ, that was shown to lead to cerebral blood flow (CBF) reductions in Tg2576 mice in vivo (Deane et al., 2003, 2012). Based on these findings (Deane et al., 2003), a clinical Phase 2/3 trial with a RAGE blocker in patients with mild Alzheimer’s disease and impaired glucose tolerance (NCT03980730 June 2019–July 2023) has been recently initiated.

    Here, Nortley et al. importantly confirmed that Aβ generates ROS in rat brain slices, which evoked release of ET1 and activated ETa receptor in pericytes to cause capillary constriction, consistent with the proposed mechanism of ET1 activation of pericytes, as we recently reviewed (Kisler et al., 2017, see Figure 3). They extended studies to live healthy human brain slices, and human tissue derived from individuals with cognitive decline to show capillary constriction in areas rich with Aβ deposits close to PDGRFβ -positive pericytes, but not aSMA-positive arterioles. Interestingly, the authors only show that constriction occurs in capillaries in vivo, in contrast to their ex vivo data and previous reports implicating ROS-mediated vascular dysfunction in arterioles as well.

    Although Nortley et al. propose that the ET1 pathway in pericytes could be a key mechanism implicated in neurodegeneration, they did not show any neuron and/or synaptic loss in their study, thus leaving open the question whether the proposed ET1-ETa mechanism can drive neurodegeneration. It has been reported, however, that accelerated pericyte loss in Tg2576 APP mice leads to both tau pathology and an overt neuron loss, suggesting that vascular damage caused by pericyte loss is a second hit in the disease process leading to neuron loss and degenerative changes in this AD model that otherwise does not occur (Sagare et al., 2013). 

    Other neuropathological studies in AD brain tissue have shown loss of pericytes associated with blood-brain barrier (BBB) breakdown and accumulation of Aβ deposits (Sengillo et al. 2013; Halliday et al. 2015). It has also been shown that Aβ intracellular accumulation kills pericytes (Ma et al., 2018; Sagare et al., 2013). Thus, while interesting, it remains to be seen how findings that Nortley et al. report fit with the existing knowledge in the field.


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    View all comments by Kassandra Kisler
  3. Vascular abnormalities have been observed in dementia since the seminal studies of Alois Alzheimer and Oscar Fisher in the early 1900s. However, vascular abnormalities have often taken a back seat to the more prominent pathologies of amyloid plaques and neurofibrillary tangles. Yet, from numerous studies it is emerging that vascular dysfunction likely has a causal role neurodegeneration and dementia (Nation et al., 2019). Recent findings from David Attwell’s laboratory underscore this point and implicate pericytes in cerebral vascular constrictions that likely contribute to cognitive impairment.

    Nortley and colleagues provide compelling evidence that in humans elevated Aβ induces pericytes to constrict brain microvasculature leading to ischemic brain regions which could contribute to neuronal damage and synaptic loss in AD. This fits into emerging evidence that vascular dysfunction has a prominent role in neurodegeneration and in particular targeting pericytes may be a viable strategy to counteract cognitive impairments induced by neurovascular dysfunction (Bell et al., 2012Halliday et al., 2015). 

    Conversely as the authors note, this study suggests that pericytes may also have a role in cognitive resilience. Numerous aged humans accumulate high levels of Aβ but seemingly do not develop cognitive impairments. It is interesting to speculate that pericytes could play a role whereby among human genetic diversity there are individuals endowed with “protective” pericytes that do not constrict in response to Aβ or are prone to compensatory vasodilation. Delving into pericyte biology and how human genetic diversity influences their contributions to pathophysiology certainly promises to be an exciting future direction.


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

    . Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2015 Mar 11; 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 Joel Blanchard
  4. The missing link. This is a must-read article on the convergence between the amyloid dysmetabolism and vascular dysfunctions.

    View all comments by Stefano Sensi

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