. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005 Aug;167(2):505-15. PubMed.


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  1. I believe the bystander effect is heavily implicated here and anyone familiar with comments on alzforum know that although autoimmunity and BBB leakage are important aspects in AD I still hold firmly to the belief that amyloid beta is an important catalyst (or cocatalyst) for immune response gone awry and for BBB leakage and TAU, CDK5 (amongst others) involved in intracellular hyperphosporylation.

    View all comments by Jacob Mack
  2. Two independent studies provided morphological evidence suggesting that accumulations of amyloid in mouse cerebral blood vessels are associated with amyloid plaques, which are typically detected in the CNS of AD patients. There is a wealth of evidence confirming vascular pathology in AD, and it was suggested years ago that amyloid plaques might originate from vessels.

    The characterization of the different morphological types of amyloid plaques has been an important research focus in our laboratory. It is becoming increasingly clear that each distinct type of plaque may arise from separate mechanisms and that the concept that diffuse plaques gradually evolve into dense-core plaques or vice versa, may not be valid.

    The Kumar paper suggested that all plaques are of vascular origin in the transgenic mouse brains; hence, in these models, there is no randomness to the distribution of the amyloid plaques. The Miao paper implied that diffuse and nonfibrillar amyloid in the cortex of the Tg-SwD1 mice remained diffuse and nonfibrillar, and that fibrillar amyloid in the thalamus was tightly associated with vessels, suggesting a vasculature origin.

    Although the primary focus of these papers was on "extracellular" amyloid (plaques), I found it surprising that there was little mention of intracellular amyloid in nearby neurons, or in smooth muscle cells as observed in AD. Perhaps the intent was to keep the paper focused on plaques, or maybe there were technical issues that did not show intracellular amyloid, or were not observed in the mouse model.

    For example, there was a loss of smooth muscle cells in the amyloid-laden vessels (Miao paper), but no discussion of the presence of amyloid in smooth muscle cells, which is frequently observed. If one was to extrapolate observations that the intracellular accumulation of amyloid in neurons is linked directly to plaque formation, it is not unreasonable to suspect a similar scenario here. Hence, amyloid could accumulate in vascular smooth muscle cells over time before they die, leaving amyloid casts (= vascular plaques). Furthermore, any cell damage, especially smooth muscle cell death, would evoke the observed inflammatory response (gliosis).

    Apparently, only diffuse, thioflavin S-negative plaques were detected in the frontotemporal cortex. Were microglia associated with these diffuse plaques detected in the prefrontal cortex, or were they only associated with "affected" vessels of the Tg-SwD1 mice? I would speculate that neither microglia nor activated astrocytes were associated with these diffuse plaques of the frontocortex, akin to the diffuse plaques observed in the human AD cerebellum and cerebrum. Therefore, if our earlier hypothesis is true—that dense-core (classical, thioflavin S-positive, etc.) plaques, but not diffuse plaques, originate from amyloid-laden neurons—then the lack of those plaques in regions of the CNS could account for the lack of consistent AD-like behaviors in such “AD” models.

    On another aspect, it was noted that “Ig occasionally stained neuronal surfaces,” but no follow-up or comment was printed. One of our recent studies reported neurodegenerative characteristics on these Ig-positive neurons.

    I still have trouble with the concept that AD is well-characterized by the steady deposition of amyloid from neurons in the brain and entering into the vasculature (Kumar, Fig. 10). Why couldn’t it be the other way around—that the brain is slowly and steadily accumulating vascular-derived amyloid, perhaps via BBB dysfunction? This issue needs to be resolved.

    View all comments by Michael R D'Andrea
  3. Regarding Dr. D’Andrea’s remarks, we studied only ThS-positive “dense” plaques and not diffuse plaques, as also suggested by the title “Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer disease are centered on vessel walls.” Within the text, however, we mostly refrained from using the term dense-core plaques (calling them dense-plaques instead). That's because the plaques observed in the studied mouse models differ from the classical dense-core plaques observed in AD, especially those observed in the Flemish APP pathology where we had earlier shown their proximity to vessels (Kumar-Singh et al. Am J Pathol, 2002).

    Secondly, as Dr. D’Andrea suggested, we indeed came across intracellular amyloid in nearby neurons and sometimes amyloid related to smooth muscle cells. However, the primary focus of our paper were dense, extracellular amyloid deposits. Similarly, our observation that “Ig occasionally stained neuronal surfaces” was there to support our observation that there are at least subtle BBB disturbances in these mouse models, as has also been observed in humans, and that clearly has other important implications, especially towards therapeutics.

    Lastly, despite a strong neuronal promoter used in these mouse models, there are some reports showing Aβ secretion from non-neuronal cells (i.e., ref. 57). Nevertheless, we have to agree that the majority of Aβ still comes from the neurons. With saturating parenchymal Aβ-degrading pathways, Aβ (especially Aβ40) is trafficked towards vessels for clearance. Although the model sums up more probable theories and published work for mouse AD models, we kept open the possibility that Aβ might also come back from vessels into brain either by receptor-mediated influx or by free diffusion taken that BBB is dysfunctional at these sites. While more studies have to be performed (especially with models that have predominantly Aβ42), one of the strongest evidence for a neurovascular Aβ flow for PSAPP and Tg2576 was that the earliest vascular deposits observed ultrastructurally occurred on the abluminal surface of capillaries and small parenchymal vessels.


    . Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. Am J Pathol. 2005 Aug;167(2):527-43. PubMed.

    . Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005 Aug;167(2):505-15. PubMed.

    . Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. Am J Pathol. 2002 Aug;161(2):507-20. PubMed.

    View all comments by Samir Kumar-Singh
  4. The source of Aβ is still an important question. We recently could show that the blood-brain barrier (BBB) endothelial cells could be important players for generating Aβ. We showed significant levels of BACE-1 in brain ECs and further show an upregulation of EC BACE-1 in a mouse AD model (hAPP-SL). These data bring back the vascular focus in AD, particularly with respect to generation of Aβ, and not just its clearance across the BBB.


    . BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease. J Cereb Blood Flow Metab. 2015 Oct 13; PubMed.

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This paper appears in the following:


  1. Amyloid-β—On or off the Wall?

Research Models

  1. Tg-SwDI (APP-Swedish,Dutch,Iowa)