Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Abstract

Background While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. Results We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.

Physiological Mechanisms Inherent to Diabetes Involved in the Development of Dementia: Alzheimer’s Disease

“…In fact, in our murine models of AD-T2D and AD-T1D, the levels of serum Aβ were reduced, indicating the inability to expel peptides from the CNS across the blood–brain barrier, while intracerebral soluble Aβ levels were increased [ 78 , 79 ]. In fact, the higher levels of soluble Aβ40 and 42 in the CNS observed in T1D and T2D are also in agreement with large synaptic loss and neuronal death observations [ 79 , 81 , 162 , 163 , 164 , 165 , 166 ]. It is feasible that the shift toward more toxic soluble species might contribute to the observed progressive synapse reduction in prediabetic and diabetic AD mice [ 50 , 167 ] and an in silico study [ 168 ].…”

“…It is feasible that the shift toward more toxic soluble species might contribute to the observed progressive synapse reduction in prediabetic and diabetic AD mice [ 50 , 167 ] and an in silico study [ 168 ]. In addition, prediabetes and T2D promote an increased accumulation of Aβ in the form of amyloid angiopathy (AAC) around blood vessels [ 81 ], which is associated with an increased risk of vascular rupture [ 169 ]. On the other hand, Aβ clearance might also be affected.…”

“…Furthermore, the pathology of AD can cause vascular damage, such as when Aβ deposition induces inflammation and endothelial damage. The pathological process resulting from vascular damage is associated with alterations in functional markers, such as increased oxidative stress, elevated proinflammatory cytokines or increased activity of matrix metalloproteinases in vessel walls [ 80 , 81 ]. These processes have been linked to neuronal death [ 82 , 83 ] responsible for dementia.…”

Oral anticoagulants: A plausible new treatment for Alzheimer's disease?

“…This deposition of Aβ in brain vessel walls is a common pathological finding in older people, it is the hallmark of CAA and has also been closely related with AD. In vivo multiphoton imaging in AD mice also showed that this vascular amyloid pathology occurs in an age‐dependent manner (Dong et al, 2010) and is further accelerated by the presence of diabetes (Vargas‐Soria et al, 2022). In fact, over 80–90% of AD patients present CAA (DeSimone et al, 2017a), which is indeed associated with the presence of the APOE‐ε4 allele, hypercholesterolemia and history of stroke (Brenowitz et al, 2015).…”

Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress

“…Cerebrovascular health is essential for vascular clearance of Aβ and alterations in neurovascular function have been implicated in CAA [2]. Suppression of the ability of neural activity to increase cerebral blood ow (CBF) (functional hyperemia), a fundamental homeostatic response of the cerebral microcirculation [15], occurs early in patients with CAA [16][17][18], whereas Aβ-induced suppression of functional hyperemia and dysfunction of the endothelial regulation of CBF have been linked to CAA in mouse models [13,[19][20][21]. Aβ-induced vascular oxidative stress and the attendant neurovascular dysregulation and damage have emerged as key factors in CAA both in mouse models [19,20] and in humans [22].…”