Amylin deposition in the brain: A second amyloid in Alzheimer disease?
TL;DR: It is hypothesized that oligomerized amylin might accumulate in the cerebrovascular system and brain parenchyma of diabetic patients and cause inflammation in the vascular system, heart, and kidneys.
Abstract: Objective
Hyperamylinemia, a common pancreatic disorder in obese and insulin-resistant patients, is known to cause amylin oligomerization and cytotoxicity in pancreatic islets, leading to β-cell mass depletion and development of type 2 diabetes. Recent data has revealed that hyperamylinemia also affects the vascular system, heart, and kidneys. We therefore hypothesized that oligomerized amylin might accumulate in the cerebrovascular system and brain parenchyma of diabetic patients.
Methods
Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer disease (AD), nondiabetic patients with AD, and age-matched healthy controls was assessed by quantitative real time polymerase chain reaction, immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay.
Results
Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late onset AD without clinically apparent diabetes. Mixed amylin and amyloid β (Aβ) deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of Aβ deposition. Tissues infiltrated by amylin showed increased interstitial space, vacuolation, spongiform change, and capillaries bent at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain.
Interpretation
Metabolic disorders and aging promote accumulation of amylin amyloid in the cerebrovascular system and gray matter, altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of Aβ from the brain, thus contributing to the etiology of AD. Ann Neurol 2013;74:517–526
Citations
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TL;DR: The evolving insights from studies on risk factors, brain imaging and neuropathology are reviewed, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction.
Abstract: Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
576 citations
Cites methods from "Amylin deposition in the brain: A s..."
...Indeed, a study from 2017 (REF.59) in a rat model of T2DM demonstrated the association of white matter rarefaction and axon demyelination with chronic vascular endothelial dysfunction, microhaemorrhages and reduced brain perfusion....
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...In addition, levels of amyloid- β and tau hyperphosphorylation in the brain were reduced in a mouse model of Alzheimer disease by treatments that improved insulin availability and/or sensitivity (experimental work reviewed in REF.66)....
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...e, f, g, h and i are adapted with permission from REF.(105), John Wiley and Sons....
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TL;DR: Possible opportunities for intervention to improve cognitive outcomes in people with type 2 diabetes are identified, and how treatment can be tailored to individual risk profiles and comorbidities is suggested.
414 citations
TL;DR: Intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD are discussed.
Abstract: Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as a potential mediator of cognitive dysfunction in T2DM, as well as in Alzheimer disease (AD). This Review highlights these observations and discusses intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD.
392 citations
Pompeu Fabra University1, Florey Institute of Neuroscience and Mental Health2, Hoffmann-La Roche3, Takeda Pharmaceutical Company4, Genentech5, Lou Ruvo Brain Institute6, Washington University in St. Louis7, Mayo Clinic8, Biogen Idec9, University of North Texas Health Science Center10, VU University Medical Center11, University of Pennsylvania12, Lundbeck13, University of Gothenburg14
TL;DR: Some of the pathological mechanisms implicated in the sporadic AD are summarized and the data for several established and novel fluid biomarkers associated with each mechanism are highlighted.
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.
337 citations
PSL Research University1, University of Michigan2, University of Akron3, University of Strasbourg4, Boston University5, National Autonomous University of Mexico6, University of California, Santa Barbara7, Pennsylvania State University8, University of Naples Federico II9, Imperial College London10, Shanghai Jiao Tong University11, Leidos12, Ton Duc Thang University13, University of Bordeaux14, University of Manchester15, Western Washington University16, Polish Academy of Sciences17, North Carolina State University18, Ben-Gurion University of the Negev19, Forschungszentrum Jülich20, University of Texas Medical Branch21, University of Minnesota22, Fudan University23, University of Paris24
TL;DR: In this paper, the authors review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease, Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research.
Abstract: Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.
300 citations
References
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TL;DR: Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
Abstract: The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
4,499 citations
"Amylin deposition in the brain: A s..." refers background in this paper
...Amylin oligomerization can injure neurons by forming membrane-permeant oligomers,(28,29) similar to the Ab oligomer-induced pathology.(25,27,31,43) Previous results demonstrated that amylin oligomers alter Ca(21) homeostasis and viability of cultured astrocytes(31) and neurons....
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TL;DR: The majority of community-dwelling older persons have brain pathology, and those with dementia most often have multiple brain pathologies, which greatly increases the odds of dementia.
Abstract: Objective: To examine the spectrum of neuropathology in persons from the Rush Memory and Aging Project, a longitudinal community-based clinical-pathologic cohort study. Methods: The study includes older persons who agreed to annual clinical evaluation and brain donation. We examined the neuropathologic diagnoses, including Alzheimer disease (AD) (NIA-Reagan Criteria), cerebral infarctions, and Parkinson disease/Lewy body disease (PD/LBD), in the first 141 autopsies. We calculated the frequency of each diagnosis alone and mixed diagnoses. We used logistic regression to compare one to multiple diagnoses on the odds of dementia. Results: Twenty persons (14.2%) had no acute or chronic brain abnormalities. The most common chronic neuropathologic diagnoses were AD (n = 80), cerebral infarctions (n = 52), and PD/LBD (n = 24). In persons with dementia (n = 50), 38.0% (n = 19) had AD and infarcts, 30.0% (n = 15) had pure AD, and 12% each had vascular dementia (n = 6) and AD with PD/LBD (n = 6). In those without dementia (n = 91), 28.6% (n = 26) had no chronic diagnostic abnormalities, 24.2% (n = 22) had pure AD, and 17.6% (n = 16) had infarctions. In persons with dementia, over 50% had multiple diagnoses (AD, PD/LBD, or infarcts), whereas, in persons without dementia, over 80% had one or no diagnosis. After accounting for age, persons with multiple diagnoses were almost three times (OR = 2.8; 95% CI = 1.2, 6.7) more likely to exhibit dementia compared to those with one pathologic diagnosis. Conclusion: The majority of community-dwelling older persons have brain pathology. Those with dementia most often have multiple brain pathologies, which greatly increases the odds of dementia.
1,524 citations
TL;DR: The presence of multiple cardiovascular risk factors at midlife substantially increases risk of late-life dementia in a dose dependent manner.
Abstract: Objective: To evaluate if midlife cardiovascular risk factors are associated with risk of late-life dementia in a large, diverse cohort. Method: The authors conducted a retrospective cohort study of 8,845 participants of a health maintenance organization who underwent health evaluations from 1964 to 1973 when they were between the ages of 40 and 44. Midlife cardiovascular risk factors included total cholesterol, diabetes, hypertension, and smoking. Diagnoses of dementia were ascertained by medical records from January 1994 to April 2003. Results: The authors identified 721 participants (8.2%) with dementia. Smoking, hypertension, high cholesterol, and diabetes at midlife were each associated with a 20 to 40% increase in risk of dementia (fully adjusted Cox proportional hazards model: HR 1.24, 95% CI 1.04 to 1.48 for hypertension, HR 1.26, 95% CI 1.08 to 1.47 for smoking, HR 1.42, 95% CI 1.22 to 1.66 for high cholesterol, and HR 1.46, 95% CI 1.19 to 1.79 for diabetes). A composite cardiovascular risk score was created using all four risk factors and was associated with dementia in a dose-dependent fashion. Compared with participants having no risk factors, the risk for dementia increased from 1.27 for having one risk factor to 2.37 for having all four risk factors (fully adjusted model: HR 2.37, 95% CI 1.10 to 5.10). Conclusion: The presence of multiple cardiovascular risk factors at midlife substantially increases risk of late-life dementia in a dose dependent manner.
1,114 citations
TL;DR: This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of I APP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.
Abstract: Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.
844 citations
"Amylin deposition in the brain: A s..." refers background in this paper
...Deleterious effects of hyperamylinemia are associated with the high propensity of human amylin to form amyloids.(21) Similar to prions(24) and other amyloidassembling proteins, the toxic species of human amylin are the soluble oligomers....
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...The AD group (n 5 14) includes brain samples from AD patients without history of T2D....
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...Amylin oligomerization and amylin deposition in the pancreas are hallmark features of T2D.(21) Recent experimental evidence(22,23) shows that hyperamylinemia also induces toxicity in peripheral organs....
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...Amylin oligomerization and amyloid deposition contribute to pancreatic b-cell dysfunction and apoptosis, leading to depletion of b-cell mass and development of T2D.(21) Oligomerized amylin also accumulates in heart(22) and kidneys,(23) accelerating diabetic heart failure....
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...Amylin oligomerization and amylin deposition in the pancreas are hallmark features of T2D.21 Recent experimental evidence22,23 shows that hyperamylinemia also induces toxicity in peripheral organs....
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TL;DR: The dementia risk score is a novel approach for the prediction of dementia risk, but should be validated and further improved to increase its predictive value.
Abstract: Summary Background Several vascular risk factors are associated with dementia. We sought to develop a simple method for the prediction of the risk of late-life dementia in people of middle age on the basis of their risk profiles. Methods Data were used from the population-based CAIDE study, which included 1409 individuals who were studied in midlife and re-examined 20 years later for signs of dementia. Several midlife vascular risk factors were studied to create the scoring tool. The score values were estimated on the basis of β coefficients and the dementia risk score was the sum of these individual scores (range 0–15). Findings Occurrence of dementia during the 20 years of follow-up was 4%. Future dementia was significantly predicted by high age (≥47 years), low education ( Interpretation The dementia risk score is a novel approach for the prediction of dementia risk, but should be validated and further improved to increase its predictive value. This approach highlights the role of vascular factors in the development of dementia and could help to identify individuals who might benefit from intensive lifestyle consultations and pharmacological interventions.
842 citations