Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. METHODS: Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. RESULTS: Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. CONCLUSIONS/INTERPRETATION: Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes. DATA AVAILABILITY: The single-cell sequencing data that supports this study are available at GEO accession GSE217665 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217665 ).

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies.

Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia-metabolism interface.

Cell proliferation and neurogenesis alterations in Alzheimer's disease and diabetes mellitus mixed murine models.

The classic neuropathological features of Alzheimer's disease (AD) are accompanied by other complications, including alterations in adult cell proliferation and neurogenesis. Moreover recent studies have shown that traditional markers of the neurogenic process, such as doublecortin (DCX), may also be expressed in CD8+ T cells and ionized calcium-binding adaptor molecule 1 (Iba1+ ) microglia, in the close proximity to senile plaques, increasing the complexity of the condition. Altered glucose tolerance, observed in metabolic alteratioins, may accelerate the neurodegenerative process and interfere with normal adult cell proliferation and neurogenesis. To further explore the role of metabolic disease in AD, we analyzed cell proliferation and neurogenesis using 5'-bromo-2'-deoxyuridine and DCX immunohistochemistry in three different mouse models of AD and metabolic alterations: APP/PS1xdb/db mice, APP/PS1 mice on a long-term high-fat diet, and APP/PS1 mice treated with streptozotozin. As reported previously, an overall reduction in cell proliferation and neurogenesis was observed after streptozotocin administration. In contrast, an increase in cell proliferation and neurogenesis was detected in neurogenic niches in 14- and 26-week-old APP/PS1xdb/db mice, accompanied by a slight increase in cortical cell proliferation. While a similar trend was observed in animals on a high-fat diet, differences were not statistically significant. We observed very few DCX+ /CD8+ cells and no DCX+ /Iba1+ cells were observed in the close proximity to senile plaques in any of the groups. Interestingly, metabolic parameters such as body weight and glucose and insulin levels were identified as reliable predictors of cell proliferation and neurogenesis in APP/PS1xdb/db mice. Furthermore, metabolic parameters were also associated with altered Aß levels in the cortex and hippocampus of APP/PS1xdb/db mice. Altogether, our data suggest that metabolic disease may also interfere with central complications in AD.

Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer's mouse model.

BACKGROUND: Diabetes is a risk factor for developing Alzheimer's disease (AD); however, the mechanism by which diabetes can promote AD pathology remains unknown. Diabetes results in diverse molecular changes in the brain, including dysregulation of glucose metabolism and loss of cerebrovascular homeostasis. Although these changes have been associated with increased Aß pathology and increased expression of glial activation markers in APPswe/PS1dE9 (APP/PS1) mice, there has been limited characterization, to date, of the neuroinflammatory changes associated with diabetic conditions. METHODS: To more fully elucidate neuroinflammatory changes associated with diabetes that may drive AD pathology, we combined the APP/PS1 mouse model with either high-fat diet (HFD, a model of pre-diabetes), the genetic db/db model of type 2 diabetes, or the streptozotocin (STZ) model of type 1 diabetes. We then used a multiplexed immunoassay to quantify cortical changes in cytokine proteins. RESULTS: Our analysis revealed that pathology associated with either db/db, HFD, or STZ models yielded upregulation of a broad profile of cytokines, including chemokines (e.g., MIP-1α, MIP-1ß, and MCP-1) and pro-inflammatory cytokines, including IL-1α, IFN-γ, and IL-3. Moreover, multivariate partial least squares regression analysis showed that combined diabetic-APP/PS1 models yielded cooperatively enhanced expression of the cytokine profile associated with each diabetic model alone. Finally, in APP/PS1xdb/db mice, we found that circulating levels of Aß1-40, Aß1-42, glucose, and insulin all correlated with cytokine expression in the brain, suggesting a strong relationship between peripheral changes and brain pathology. CONCLUSIONS: Altogether, our multiplexed analysis of cytokines shows that Alzheimer's and diabetic pathologies cooperate to enhance profiles of cytokines reported to be involved in both diseases. Moreover, since many of the identified cytokines promote neuronal injury, Aß and tau pathology, and breakdown of the blood-brain barrier, our data suggest that neuroinflammation may mediate the effects of diabetes on AD pathogenesis. Therefore, strategies targeting neuroinflammatory signaling, as well as metabolic control, may provide a promising strategy for intervening in the development of diabetes-associated AD.

Germinal Matrix-Intraventricular Hemorrhage of the Preterm Newborn and Preclinical Models: Inflammatory Considerations.

The germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most important complications of the preterm newborn. Since these children are born at a critical time in brain development, they can develop short and long term neurological, sensory, cognitive and motor disabilities depending on the severity of the GM-IVH. In addition, hemorrhage triggers a microglia-mediated inflammatory response that damages the tissue adjacent to the injury. Nevertheless, a neuroprotective and neuroreparative role of the microglia has also been described, suggesting that neonatal microglia may have unique functions. While the implication of the inflammatory process in GM-IVH is well established, the difficulty to access a very delicate population has lead to the development of animal models that resemble the pathological features of GM-IVH. Genetically modified models and lesions induced by local administration of glycerol, collagenase or blood have been used to study associated inflammatory mechanisms as well as therapeutic targets. In the present study we review the GM-IVH complications, with special interest in inflammatory response and the role of microglia, both in patients and animal models, and we analyze specific proteins and cytokines that are currently under study as feasible predictors of GM-IVH evolution and prognosis.

Review of the Effect of Natural Compounds and Extracts on Neurodegeneration in Animal Models of Diabetes Mellitus.

Diabetes mellitus is a chronic metabolic disease with a high prevalence in the Western population. It is characterized by pancreas failure to produce insulin, which involves high blood glucose levels. The two main forms of diabetes are type 1 and type 2 diabetes, which correspond with >85% of the cases. Diabetes shows several associated alterations including vascular dysfunction, neuropathies as well as central complications. Brain alterations in diabetes are widely studied; however, the mechanisms implicated have not been completely elucidated. Diabetic brain shows a wide profile of micro and macrostructural changes, such as neurovascular deterioration or neuroinflammation leading to neurodegeneration and progressive cognition dysfunction. Natural compounds (single isolated compounds and/or natural extracts) have been widely assessed in metabolic disorders and many of them have also shown antioxidant, antiinflamatory and neuroprotective properties at central level. This work reviews natural compounds with brain neuroprotective activities, taking into account several therapeutic targets: Inflammation and oxidative stress, vascular damage, neuronal loss or cognitive impairment. Altogether, a wide range of natural extracts and compounds contribute to limit neurodegeneration and cognitive dysfunction under diabetic state. Therefore, they could broaden therapeutic alternatives to reduce or slow down complications associated with diabetes at central level.

Human tau increases amyloid ß plaque size but not amyloid ß-mediated synapse loss in a novel mouse model of Alzheimer's disease.

Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aß) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aß. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aß and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aß-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aß at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss.

Low-voltage pattern and absence of sleep-wake cycles are associated with severe hemorrhage and death in very preterm infants.

UNLABELLED: Amplitude integrated electroencephalogaphy (aEEG) is becoming an important tool for the assessment of cerebral activity in preterm newborns. Describing the relationship between early aEEG patterns and intraventricular hemorrhage (IVH) can improve our knowledge of neurological injury in the preterm newborn. The aim of this prospective study was to identify early changes in the aEEG in premature newborns that could be associated to severe neurological lesion/death. Preterm newborns with a birth weight ≤1,500 g and/or 32 weeks of gestation were included. aEEG monitoring was performed during the first 72 h of life. A qualitative analysis of the aEEG recordings was performed, based on continuity, sleep-wake cycles (SWCs), inferior lower margin amplitude (LMA), and bandwidth (BW). Key outcomes were severe IVH and/or death. Ninety-two subjects were included (mean gestational age 28 weeks). In 28.6 % of subjects with HIV III/IHP, a low-voltage pattern was observed. A statistically significant relationship was found between low-voltage tracings and death and neurological lesion/death. Absent SWCs during the first 72 h were also related to death. CONCLUSION: Early aEEG patterns can be predictive of neurological outcome in the preterm newborn. Low-voltage tracing and absence of SWCs are associated with severe neurological lesions/death.

Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.

Glycogen Synthase Kinase-3ß Inhibitor VP3.15 Ameliorates Neurogenesis, Neuronal Loss and Cognitive Impairment in a Model of Germinal Matrix-intraventricular Hemorrhage of the Preterm Newborn.

Advances in neonatology have significantly reduced mortality rates due to prematurity. However, complications of prematurity have barely changed in recent decades. Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications of prematurity, and these children are prone to suffer short- and long-term sequelae, including cerebral palsy, cognitive and motor impairments, or neuropsychiatric disorders. Nevertheless, GM-IVH has no successful treatment. VP3.15 is a small, heterocyclic molecule of the 5-imino-1,2,4-thiadiazole family with a dual action as a phosphodiesterase 7 and glycogen synthase kinase-3ß (GSK-3ß) inhibitor. VP3.15 reduces neuroinflammation and neuronal loss in other neurodegenerative disorders and might ameliorate complications associated with GM-IVH. We administered VP3.15 to a mouse model of GM-IVH. VP3.15 reduces the presence of hemorrhages and microglia in the short (P14) and long (P110) term. It ameliorates brain atrophy and ventricle enlargement while limiting tau hyperphosphorylation and neuronal and myelin basic protein loss. VP3.15 also improves proliferation and neurogenesis as well as cognition after the insult. Interestingly, plasma gelsolin levels, a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the beneficial effects of VP3.15 in GM-IVH by ameliorating brain neuroinflammatory, vascular and white matter damage, ultimately improving cognitive impairment associated with GM-IVH.

Rescue of neurogenesis and age-associated cognitive decline in SAMP8 mouse: Role of transforming growth factor-alpha.

Neuropathological aging is associated with memory impairment and cognitive decline, affecting several brain areas including the neurogenic niche of the dentate gyrus of the hippocampus (DG). In the healthy brain, homeostatic mechanisms regulate neurogenesis within the DG to facilitate the continuous generation of neurons from neural stem cells (NSC). Nevertheless, aging reduces the number of activated neural stem cells and diminishes the number of newly generated neurons. Strategies that promote neurogenesis in the DG may improve cognitive performance in the elderly resulting in the development of treatments to prevent the progression of neurological disorders in the aged population. Our work is aimed at discovering targeting molecules to be used in the design of pharmacological agents that prevent the neurological effects of brain aging. We study the effect of age on hippocampal neurogenesis using the SAMP8 mouse as a model of neuropathological aging. We show that in 6-month-old SAMP8 mice, episodic and spatial memory are impaired; concomitantly, the generation of neuroblasts and neurons is reduced and the generation of astrocytes is increased in this model. The novelty of our work resides in the fact that treatment of SAMP8 mice with a transforming growth factor-alpha (TGFα) targeting molecule prevents the observed defects, positively regulating neurogenesis and improving cognitive performance. This compound facilitates the release of TGFα in vitro and in vivo and activates signaling pathways initiated by this growth factor. We conclude that compounds of this kind that stimulate neurogenesis may be useful to counteract the neurological effects of pathological aging.

Increased Aß production prompts the onset of glucose intolerance and insulin resistance.

Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. ß-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented ß-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aß production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.

Cerebrovascular lesions induce transient ß-amyloid deposition.

Previous clinical studies have documented a close relationship between cerebrovascular disease and risk of Alzheimer's disease. We examined possible mechanistic interactions through use of experimental stroke models in a transgenic mouse model of ß-amyloid deposition (APPswe/PS1dE9). Following middle cerebral artery occlusion, we observed a rapid increase in amyloid plaque burden in the region surrounding the infarction. In human tissue samples, however, we were unable to detect a localized increase in amyloid burden adjacent to cerebral infarcts. To resolve this discrepancy, we generated cerebral microstrokes in amyloid precursor protein mouse models with the photosensitive dye Rose bengal, and monitored plaque formation in real time using multiphoton microscopy. We observed a striking increase in the number of new plaques and amyloid angiopathy in the area immediately surrounding the infarcted area; however, the effect was transient, potentially resolving the discord between mouse and human tissue. We did not detect changes in candidate proteins related to ß-amyloid generation or degradation such as ß-amyloid-converting enzyme, amyloid precursor protein, presenilin 1, neprylisin or insulin-degrading enzyme. Together, these results demonstrate that strokes can trigger accelerated amyloid deposition, most likely through interference with amyloid clearance pathways. Additionally, this study indicates that focal ischaemia provides an experimental paradigm in which to study the mechanisms of plaque seeding and growth.

Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques.

Synapse loss correlates with a cognitive decline in Alzheimer's disease (AD), but whether this is caused by fibrillar deposits known as senile plaques or soluble oligomeric forms of amyloid beta (Abeta) is controversial. By using array tomography, a technique that combines ultrathin sectioning of tissue with immunofluorescence, allowing precise quantification of small structures, such as synapses, we have tested the hypothesis that oligomeric Abeta surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric Abeta. Analysis of >14,000 synapses (represented by PSD95-stained excitatory synapses) shows that there is a 60% loss of excitatory synapses in the halo of oligomeric Abeta surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 microm from a plaque in an approximately linear fashion (linear regression, r(2) = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric Abeta associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric Abeta. The proportion of excitatory synapses associated with Abeta correlates with decreasing density (correlation, -0.588; P < 0.0001). These data show that senile plaques are a potential reservoir of oligomeric Abeta, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of "plaque" vs. "oligomeric Abeta" as the synaptotoxic species in the brain of AD patients.

Caffeine Restores Neuronal Damage and Inflammatory Response in a Model of Intraventricular Hemorrhage of the Preterm Newborn.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

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

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-ß (Aß) 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 Aß. METHODS: To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aß 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 Aß. 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 Aß deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.

Common pathways in dementia and diabetic retinopathy: understanding the mechanisms of diabetes-related cognitive decline.

Type 2 diabetes (T2D) is associated with multiple comorbidities, including diabetic retinopathy (DR) and cognitive decline, and T2D patients have a significantly higher risk of developing Alzheimer's disease (AD). Both DR and AD are characterized by a number of pathological mechanisms that coalesce around the neurovascular unit, including neuroinflammation and degeneration, vascular degeneration, and glial activation. Chronic hyperglycemia and insulin resistance also play a significant role, leading to activation of pathological mechanisms such as increased oxidative stress and the accumulation of advanced glycation end-products (AGEs). Understanding these common pathways and the degree to which they occur simultaneously in the brain and retina during diabetes will provide avenues to identify T2D patients at risk of cognitive decline.

Mitochondria-ER contacts and glucose: the powerhouse of Alzheimer's disease?

A mechanism involving endoplasmic reticulum-mitochondria contacts noted in diabetes mellitus may explain the neurodegeneration and amyloidogenesis observed in these patients. Urolithin A, a metabolite found in the gut microbiome, is proposed as a therapeutic strategy for the treatment of the diabetes-related dementia.

Role of liraglutide in Alzheimer's disease pathology.

BACKGROUND: The described relationship between Alzheimer's disease (AD) and type 2 diabetes (T2D) and the fact that AD has no succesful treatment has led to the study of antidiabetic drugs that may limit or slow down AD pathology. MAIN BODY: Although T2D treatment has evident limitations, options are increasing including glucagon-like peptide 1 analogs. Among these, liraglutide (LRGT) is commonly used by T2D patients to improve ß cell function and suppress glucagon to restore normoglycaemia. Interestingly, LRGT also counterbalances altered brain metabolism and has anti-inflammatory properties. Previous studies have reported its capacity to reduce AD pathology, including amyloid production and deposition, tau hyperphosphorylation, or neuronal and synaptic loss in animal models of AD, accompanied by cognitive improvement. Given the beneficial effects of LRGT at central level, studies in patients have been carried out, showing modest beneficial effects. At present, the ELAD trial (Evaluating Liraglutide in Alzheimer's Disease NCT01843075) is an ongoing phase IIb study in patients with mild AD. In this minireview, we resume the outcomes of LRGT treatment in preclinical models of AD as well as the available results in patients up to date. CONCLUSION: The effects of LRGT on animal models show significant benefits in AD pathology and cognitive impairment. While studies in patients are limited, ongoing clinical trials will probably provide more definitive conclusions on the role of LRGT in AD patients.

Alzheimer's Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models.

Alzheimer's disease (AD) is the most common cause of dementia. Epidemiological studies show the association between AD and type 2 diabetes (T2DM), although the mechanisms are not fully understood. Dietary habits and lifestyle, that are risk factors in both diseases, strongly modulate gut microbiota composition. Also, the brain-gut axis plays a relevant role in AD, diabetes and inflammation, through products of bacterial metabolism, like short-chain fatty acids. We provide a comprehensive review of current literature on the relation between dysbiosis, altered inflammatory cytokines profile and microglia in preclinical models of AD, T2DM and models that reproduce both diseases as commonly observed in the clinic. Increased proinflammatory cytokines, such as IL-1ß and TNF-α, are widely detected. Microbiome analysis shows alterations in Actinobacteria, Bacteroidetes or Firmicutes phyla, among others. Altered α- and ß-diversity is observed in mice depending on genotype, gender and age; therefore, alterations in bacteria taxa highly depend on the models and approaches. We also review the use of pre- and probiotic supplements, that by favoring a healthy microbiome ameliorate AD and T2DM pathologies. Whereas extensive studies have been carried out, further research would be necessary to fully understand the relation between diet, microbiome and inflammation in AD and T2DM.