APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

Manocha, Gunjan D.; Floden, Angela M.; Rausch, Keiko; Kulas, Joshua A.; McGregor, Brett A.; Rojanathammanee, Lalida; Puig, Kelley R.; Karki, Sanjib; Nichols, Michael R.; Darland, Diane C.; Porter, James E.; Combs, Colin K.

doi:10.1523/jneurosci.4654-15.2016

Cited by 55 publications

(49 citation statements)

References 86 publications

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“…Since we and others have previously observed that the APP/PS1 line accumulates brain Aβ deposits in an age dependent manner (Gordon, et al 2002; Manocha, et al 2016), WT and transgenic mouse pancreas were immunostained to detect Aβ at two and twelve months of age (Fig 3B). A faint amount of immunoreactivity was observed in 12 month old APP/PS1 islets relative to the APP −/− and WT mice likely due to the anti-Aβ antibody, 4G8, cross-reacting with full length APP.…”

Section: Resultsmentioning

confidence: 97%

Amyloid precursor protein in pancreatic islets

Kulas

Puig

Combs

2017

Journal of Endocrinology

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The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well characterized consequence of type 1 and type 2 diabetes. In this study we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrates the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by western blot from C57BL/6 (WT), APP−/−, and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

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Section: Resultsmentioning

confidence: 97%

Amyloid precursor protein in pancreatic islets

Kulas

Puig

Combs

2017

Journal of Endocrinology

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“…There is evidence that neuroinflammation is an important pathogenetic component of AD [34,35] which is clearly demonstrated also in amyloid precursor protein (APP) overexpressing transgenic mouse models. [36,37] Immunohistochemistry of brain sections from wildtype and 5xFAD transgenic animals revealed prominent microgliosis in 5xFAD mice as evidenced by the increased number of Iba-1-and CD-45-positive cells (both markers of activated microglia) in the hippocampus (Figure 2b,c). The combination of memantine with melatonin and each of the singly administered drugs showed a significant impact on the number of Iba-1-positive cells in dorsal (F 3,34 = 37,73; P < 0.0001, Bonferroni P < 0.001) and ventral (F 3,34 = 64,82; P < 0.0001, Bonferroni P < 0.0001) hippocampus of 5xFAD mice.…”

Section: Neuroinflammation In 5xfad Micementioning

confidence: 99%

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Jürgenson

Zharkovskaja

Noortoots

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Alzheimer's disease (AD) is a neurodegenerative disorder with no cure. Limited treatment options available today do not offer solutions to slow or stop any of the suspected causes. The current medications used for the symptomatic treatment of AD include memantine and acetylcholine esterase inhibitors. Some studies suggest that melatonin could also be used in AD patients due to its sleep‐improving properties. Methods In this study, we evaluated whether a combination of memantine with melatonin, administered for 32 days in drinking water, was more effective than either drug alone with respect to Aβ aggregates, neuroinflammation and cognition in the double transgenic APP/PS1 (5xFAD) mouse model of AD. Key findings In this study, chronic administration of memantine with melatonin improved episodic memory in the object recognition test and reduced the number of amyloid aggregates and reactive microgliosis in the brains of 5xFAD mice. Although administration of memantine or melatonin alone also reduced the number of amyloid aggregates and inflammation in brain, this study shows a clear benefit of the drug combination, which had a significantly stronger effect in this amyloid‐dominant mouse model of AD. Conclusion Our data suggest considerable potential for the use of memantine with melatonin in patients with AD.

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“…On the contrary, (pre‐)clinical trials including non‐steroidal anti‐inflammatory drugs (NSAIDs) suggested that inhibiting the immune system may also be of benefit in reducing the disease incidence or slowing down AD progression (Stewart et al , ; Anthony et al , ; in t' Veld et al , ; Zandi et al , ; Monsonego & Weiner, ; Heneka et al , ; Yip et al , ). Additionally, microglia can be activated by Αβ resulting in secretion of inflammatory cytokines that can harm neurons and provoke toxicity (Meda et al , ; Giulian et al , ; Combs et al , ; Manocha et al , ). It is therefore not clear whether microglial activation is beneficial or detrimental for disease progression (Morgan et al , ; Wyss‐Coray, ; Gandy & Heppner, ).…”

Section: Introductionmentioning

confidence: 99%

Young microglia restore amyloid plaque clearance of aged microglia

et al. 2016

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Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.

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APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

Cited by 55 publications

References 86 publications

Amyloid precursor protein in pancreatic islets

Amyloid precursor protein in pancreatic islets

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Young microglia restore amyloid plaque clearance of aged microglia

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