Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease

Held, Friederike; Morris, Alan; Pirici, Daniel; Niklass, Solveig; Sharp, Matthew MacGregor; Garz, Cornelia; Assmann, Anne; Heinze, Hans‐Jochen; Schreiber, Frank; Carare, Roxana O.; Schreiber, Stefanie

doi:10.1042/cs20170004

Cited by 41 publications

(28 citation statements)

References 42 publications

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“…The association of the CAA‐predominant pathology group with arterial hypertension furthermore indicates that this condition could affect the leading site of A β maturation and, thereby, might act as additional risk factor for A β seeding and maturation. This is indeed supported by the development of CAA in a rat model for hypertension . Thus, arterial hypertension should be taken into account for therapeutic intervention because it might modify the pathological picture of AD to the CAA‐predominant pattern.…”

Section: Discussionmentioning

confidence: 74%

Modified amyloid variants in pathological subgroups of β‐amyloidosis

Gerth

Kumar

Upadhaya

et al. 2018

Ann Clin Transl Neurol

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ObjectiveAmyloid β (Aβ) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post‐translationally modified Aβ in plaques characterizes distinct biochemical stages of Aβ maturation. However, the molecular composition of vascular Aβ deposits in CAA and its relation to plaques remain enigmatic.MethodsVascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aβ in the medial temporal and occipital lobe of 24 controls, 27 pathologically‐defined preclinical AD, and 20 symptomatic AD cases.ResultsSequential deposition of Aβ in CAA resembled Aβ maturation in plaques and enabled the distinction of three biochemical stages of CAA. B‐CAA stage 1 was characterized by deposition of Aβ in the absence of pyroglutaminated Aβ N3pE and phosphorylated Aβ pS8. B‐CAA stage 2 showed additional Aβ N3pE and B‐CAA stage 3 additional Aβ pS8. Based on the Aβ maturation staging in CAA and plaques, three case groups for Aβ pathology could be distinguished: group 1 with advanced Aβ maturation in CAA; group 2 with equal Aβ maturation in CAA and plaques; group 3 with advanced Aβ maturation in plaques. All symptomatic AD cases presented with end‐stage plaque maturation, whereas CAA could exhibit immature Aβ deposits. Notably, Aβ pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia.InterpretationBalance of Aβ maturation in CAA and plaques defines distinct pathological subgroups of β‐amyloidosis. The association of CAA‐related Aβ maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aβ pathology subgroups, and the subgroup‐related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.

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Section: Discussionmentioning

confidence: 74%

Modified amyloid variants in pathological subgroups of β‐amyloidosis

Gerth

Kumar

Upadhaya

et al. 2018

Ann Clin Transl Neurol

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“…Aβ may critically influence cerebral small vessel disease in hemorrhagic stroke, and its parenchymal and vascular accumulation in the brains of SHRSP rats has been reported previously [20,35]. Thus, we explored the possible involvement of AT1R and the impact of its blockade on the cerebral content of Aβ in SHRSP.…”

Section: Losartan Reduces Inflammatory Response and Aβ In The Brains mentioning

confidence: 85%

Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats

et al. 2019

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The contribution of the local angiotensin receptor system to neuroinflammation, impaired neurogenesis, and amyloid beta (Aβ) accumulation in Alzheimer's disease (AD) and in hypertension is consistent with the remarkable neuroprotection provided by angiotensin receptor blockers (ARBs) independent of their blood pressure-lowering effect. Considering the causal relationship between hypertension and AD and that targeting cerebrovascular pathology with ARBs does not necessarily require their systemic effects, we tested intranasal losartan in the rat model of chronic hypertension (spontaneously hypertensive strokeprone rats, SHRSP). Intranasal losartan at a subdepressor dose decreased mortality, neuroinflammation, and perivascular content of Aβ by enhancing key players in its metabolism and clearance, including insulin-degrading enzyme, neprilysin, and transthyretin. Furthermore, this treatment improved neurologic deficits and increased brain IL-10 concentration, hippocampal cell survival, neurogenesis, and choroid plexus cell proliferation in SHRSP. Losartan (1 μM) also reduced LDH release from cultured astroglial cells in response to toxic glutamate concentrations. This effect was completely blunted by IL-10 antibodies. These findings suggest that intranasal ARB treatment is a neuroprotective, neurogenesis-inducing, and Aβ-decreasing strategy for the treatment of hypertensive stroke and cerebral amyloid angiopathy acting at least partly through the IL-10 pathway.

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“…Although the BBB and perivascular clearance pathways play a major role in Aβ level regulation, the Aβ amount is also regulated (i.e., degraded) by a large set of proteases with diverse characteristics [76,77]. It has been demonstrated that insulin-degrading enzyme, neprilysin, and endothelin-converting enzymes 1 and 2 are strongly involved in Aβ clearance [78].…”

Section: Enzymatic Aβ Clearancementioning

confidence: 99%

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

Goulay

Romo

Hol

et al. 2019

Transl. Stroke Res.

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Stroke and Alzheimer's disease (AD) are cerebral pathologies with high socioeconomic impact that can occur together and mutually interact. Vascular factors predisposing to cerebrovascular disease have also been specifically associated with development of AD, and acute stroke is known to increase the risk to develop dementia. Despite the apparent association, it remains unknown how acute cerebrovascular disease and development of AD are precisely linked and act on each other. It has been suggested that this interaction is strongly related to vascular deposition of amyloid-β (Aβ), i.e., cerebral amyloid angiopathy (CAA). Furthermore, the blood-brain barrier (BBB), perivascular space, and the glymphatic system, the latter proposedly responsible for the drainage of solutes from the brain parenchyma, may represent key pathophysiological pathways linking stroke, Aβ deposition, and dementia. In this review, we propose a hypothetic connection between CAA, stroke, perivascular space integrity, and dementia. Based on relevant pre-clinical research and a few clinical case reports, we speculate that impaired perivascular space integrity, inflammation, hypoxia, and BBB breakdown after stroke can lead to accelerated deposition of Aβ within brain parenchyma and cerebral vessel walls or exacerbation of CAA. The deposition of Aβ in the parenchyma would then be the initiating event leading to synaptic dysfunction, inducing cognitive decline and dementia. Maintaining the clearance of Aβ after stroke could offer a new therapeutic approach to prevent post-stroke cognitive impairment and development into dementia.

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Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease

Cited by 41 publications

References 42 publications

Modified amyloid variants in pathological subgroups of β‐amyloidosis

Modified amyloid variants in pathological subgroups of β‐amyloidosis

Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

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