Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

Trujillo‐Estrada, Laura; Nguyen, Cassidy; Cunha, Celia Da; Cai, Lena; Forner, Stefânia; Martini, Alessandra Cadete; Ager, Rahasson R.; Prieto, G. Aleph; Cotman, Carl W.; Baglietto‐Vargas, David; LaFerla, Frank M.

doi:10.1111/acel.12919

Cited by 19 publications

(24 citation statements)

References 64 publications

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“…While the two conditions share some attributes, the evidence linking AD to T2D is weak. The Rush longitudinal cohort study of aging found that neither HbA1c nor diabetes was correlated with plaque, tau, or infarct pathology ( Pruzin et al, 2017 ); cognitive and synaptic deficits in a model of T2D are independent of tau ( Trujillo-Estrada et al, 2019 ). T2D confers no elevation in the accumulation of Aβ or neurofibrillary pathology ( Beeri et al, 2005 ; Heitner and Dickson, 1997 ; Peila et al, 2002 ; Roberts et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood

Hendrix¹,

Davis

et al. 2021

Neurobiology of Aging

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Alzheimer’s disease (AD) is associated with disturbances in blood glucose regulation, and type-2 diabetes elevates the risk for dementia. A role for amyloid-β peptide (Aβ) in linking these age-related conditions has been proposed, tested primarily in transgenic mouse lines that overexpress mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line (“Aβ 42 -tg”), which produces extracellular Aβ 1–42 in the CNS without elevation of APP. We also looked for interactions with diet-induced obesity (DIO) resulting from a high-fat, high-sucrose (“western”) diet. Aβ 42 -tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, Aβ 1–42 accumulation did not, and the impacts of DIO and Aβ on glucose tolerance were merely additive. Aβ 42 -tg mice exhibited no significant differences from wild-type in insulin production, body weight, lipidemia, appetite, physical activity, respiratory quotient, an-/orexigenic factors, or inflammatory factors. These negative findings suggested that the phenotype in these mice arose from perturbation of glucose excursion in an insulin-independent tissue. To wit, cerebral cortex of Aβ 42 -tg mice had reduced glucose utilization, similar to human patients with AD. This was associated with insufficient trafficking of glucose transporter 1 to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower cerebral metabolic rate of glucose and diminished function of parenchymal glucose transporter 1 indicate that aberrant regulation of blood glucose in AD likely reflects a central phenomenon, resulting from the effects of Aβ on cerebral parenchyma, rather than a generalized disruption of hypothalamic or peripheral endocrinology. The involvement of a specific glucose transporter in this deficit provides a new target for the design of AD therapies.

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Section: Discussionmentioning

confidence: 99%

Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood

Hendrix¹,

Davis

et al. 2021

Neurobiology of Aging

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“…These could be related to impaired insulin signaling in the brain resulting in tau hyperphosphorylation, one of the pathological features in AD. Several studies have shown insulin to regulate tau phosphorylation [ 11 , 18 , 19 ].…”

Section: Reviewmentioning

confidence: 99%

“…Postmortem studies have shown an increase in hyperphosphorylated tau in patients with DM compared to age-matched controls suggesting a link between DM and AD [ 18 ]. Additionally, western blot analysis has shown a significant increase in the total tau protein present in human patients with both DM and AD, in addition to non-significant hyperphosphorylation at the Ser202/Thr205 and pThr231 epitopes [ 18 ]. It has also been shown that insulin resistance increases as we age, leading to more susceptibility to diseases like AD [ 12 ].…”

Section: Reviewmentioning

confidence: 99%

The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease

Hobday¹,

Parmar²

2021

Cureus

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Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between DM and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles. In DM, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3β (GSK-3β) activity showing to enhance tau phosphorylation. In DM and AD, GSK-3β signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why DM patients have an increased risk of developing AD with disease progression and aging. Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in DM have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between DM and AD as it relates to tau pathology. More understanding of the link between DM and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.

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“…These inflammatory mediators can activate brain-residing microglia and astrocytes, leading to CNS inflammation and synaptic dysfunction [ 23 ]. Recent study further demonstrated that insulin-signaling dysregulation and tau pathology are critical for T1DM-associated cognitive/synaptic deficits, while chronic inflammation plays an important role in T2DM-associated cognitive/synaptic impairments [ 2 ]. Therefore, alleviating inflammation may represent a promising therapeutic option to ameliorate cognitive dysfunction and dementia in both T2DM and AD.…”

Section: Discussionmentioning

confidence: 99%

“…Type 2 diabetes mellitus (T2DM) is the most common chronic metabolic disease characterized by insulin resistance and chronic inflammation, leading to hyperglycemia and accelerated aging [ 1 , 2 ]. Cognitive impairment is a well-known complication of T2DM; however, the precise mechanism through which T2DM metabolic disturbances contribute to cognitive decline remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Co-administration of berberine/gypenosides/bifendate ameliorates metabolic disturbance but not memory impairment in type 2 diabetic mice

Zhang

Guo

et al. 2021

Heliyon

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Cognitive impairment is a well-known complication of Type 2 diabetes mellitus (T2DM) characterized by cellular insulin resistance, chronic inflammation, and metabolic disturbances. Berberine, gypenosides and bifendate are traditional Chinese herbal medicines with multiple pharmacological activities including anti-inflammation, anti-oxidant, metabolism improvement and memory improvement. To investigate whether they have synergistic effect on T2DM metabolic syndrome and associated memory impairment, we measured in this study the effect of a low dose of berberine/gypenosides/bifendate (BGB) co-administration on metabolism and memory performance of T2DM model mice. We found that BGB co-administration ameliorated metabolic abnormalities of both high-fat diet/streptozotocin (STZ)-induced T2DM mice and db/db mice. However, it did not alleviate memory impairment in either type of T2DM model mice. Since neither berberine, gypenosides nor bifendate alone at the low dose is effective, we presume that BGB co-administration has synergistic action on T2DM metabolic syndrome. In addition, our findings suggest that higher doses of BGB might be required to ameliorate memory impairment than metabolic disturbance associated with T2DM.

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Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

Cited by 19 publications

References 64 publications

Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood

Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood

The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease

Co-administration of berberine/gypenosides/bifendate ameliorates metabolic disturbance but not memory impairment in type 2 diabetic mice

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