scholarly journals Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

ASN NEURO ◽  
2017 ◽  
Vol 9 (4) ◽  
pp. 175909141771920 ◽  
Author(s):  
Felecia M. Marottoli ◽  
Yuriko Katsumata ◽  
Kevin P. Koster ◽  
Riya Thomas ◽  
David W. Fardo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Interactive Effect ◽  
Amyloid Β ◽  
Collective Effects ◽  
Peripheral Inflammation ◽  
Amyloid Angiopathy ◽  
Apolipoprotein E4 ◽  
Cerebrovascular Dysfunction

Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 ( APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/−/ APOE+/+ (EFAD+)] and noncarriers [5xFAD−/−/ APOE+/+ (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.

Functional protection in J20/VLW mice: a model of non-demented with Alzheimer’s disease neuropathology

Brain ◽  
2021 ◽  
Author(s):  
Eva Dávila-Bouziguet ◽  
Arnau Casòliba-Melich ◽  
Georgina Targa-Fabra ◽  
Lorena Galera-López ◽  
Andrés Ozaita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Rhythmic Activity ◽  
Hyperphosphorylated Tau ◽  
Field Potentials ◽  
Suitable Animal Model ◽  
Phosphorylation Pattern ◽  
Oscillatory Rhythms

Abstract Alzheimer’s disease comprises amyloid-β and hyperphosphorylated Tau accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimer’s disease Neuropathology (NDAN) defines a novel clinical entity with amyloid-β and Tau pathologies but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models of NDAN are currently unavailable. We demonstrate that J20/VLW mice (accumulating amyloid-β and hyperphosphorylated Tau) exhibit preserved hippocampal rhythmic activity and cognition, as opposed to J20 and VLW animals, which show significant alterations. Furthermore, we show that the overexpression of mutant human Tau in coexistence with amyloid-β accumulation renders a particular hyperphosphorylated Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model in which to explore the mechanisms driving cognitive preservation in NDAN. Moreover, they suggest that a differential Tau phosphorylation pattern in hippocampal interneurons prevents the loss of GABAergic septohippocampal innervation and alterations in local field potentials, thereby avoiding cognitive deficits.

scholarly journals The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients

2013 ◽  
Vol 33 (8) ◽  
pp. 1251-1258 ◽  
Author(s):  
Karin Hultman ◽  
Sidney Strickland ◽  
Erin H Norris
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Apoe Genotype ◽  
Postmortem Brain ◽  
Amyloid Angiopathy ◽  
Apoe Ε4 ◽  
Cerebrovascular Dysfunction ◽  
Postmortem Brain Tissue ◽  
Clotting Protein

Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Ab), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.

scholarly journals Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

2019 ◽  
Vol 22 (3) ◽  
pp. 401-412 ◽  
Author(s):  
Evandro F. Fang ◽  
Yujun Hou ◽  
Konstantinos Palikaras ◽  
Bryan A. Adriaanse ◽  
Jesse S. Kerr ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Tau Pathology

Cognitive enhancement of volatile oil from the stems of Schisandra chinensis Baill. in Alzheimer’s disease rats

2018 ◽  
Vol 96 (6) ◽  
pp. 550-555 ◽  
Author(s):  
Bingyou Yang ◽  
Bo Liu ◽  
Yan Liu ◽  
Hua Han ◽  
Haixue Kuang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Volatile Oil ◽  
Gas Chromatography Mass Spectrometry ◽  
Morris Water Maze Test ◽  
Schisandra Chinensis ◽  
Nerve Growth ◽  
Necrosis Factor

The volatile oil (VO), extracted from the stems of Schisandra chinensis Baill. (SCS), was separated and identified by gas chromatography – mass spectrometry. The study was devised to investigate the effects of VO on oxidative stress and cognitive deficits induced by amyloid-β (Aβ(1-42)). Alzheimer’s disease (AD) models were established by injecting Aβ(1-42) into the rat hippocampus and the effects of learning and memory were observed by a Morris water maze test, immunohistological alterations, and correlative indicators covering nerve growth (brain-derived neurotrophic factor, glial-cell-derived trophic factor, and nerve growth factor), interleukin 1β, tumor necrosis factor, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), glial fibrillary acidic protein (GFAP), and microglial CD11b in AD rats. And activities of SOD, MDA, and GSH-Px were ameliorated by VO. The neurotrophic factors GFAP and microglial CD11b were noticeably improved in histopathologic changes. These data suggested that VO from SCS had potential activities for the prevention and treatment of AD.

scholarly journals Identification of small molecule drugs that target apolipoprotein E4‐catalyzed amyloid‐β fibrillization: A new therapeutic approach to Alzheimer’s disease

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
Noah R Johnson ◽  
Athena Ching‐Jung Wang ◽  
Christina M Coughlan ◽  
Stefan H Sillau ◽  
Esteban M Lucero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Therapeutic Approach ◽  
Amyloid Β ◽  
Apolipoprotein E4 ◽  
Small Molecule Drugs

scholarly journals Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration

2013 ◽  
Vol 16 (6) ◽  
pp. 1351-1360 ◽  
Author(s):  
Marta Dobarro ◽  
Lourdes Orejana ◽  
Norberto Aguirre ◽  
Maria J. Ramírez
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Object Recognition Test ◽  
Adrenergic Antagonist ◽  
Propranolol Treatment

Abstract Chronic exposure to glucocorticoids might result not only in insulin resistance or cognitive deficits, but it is also considered as a risk factor for pathologies such as Alzheimer's disease. Propranolol is a β-adrenergic antagonist commonly used in the treatment of hypertension or acute anxiety. The effects of propranolol (5 mg/kg) have been tested in a model of chronic corticosterone administration (100 µg/ml, 4 wk) in drinking water. Corticosterone administration led to cognitive impairment in the novel object recognition test that was reversed by propranolol. Increased levels of Aβ in the hippocampus of corticosterone-treated mice were counteracted by propranolol treatment, purportedly through an increased IDE expression. Chronic corticosterone treatment induced responses characteristic of insulin resistance, as increased peripheral insulin levels, decreased activation of the insulin receptor (pIR) and decreased associated intracellular pathways (pAkt). These effects might be related to a decreased c-Jun N terminal kinase 1 expression. Again, propranolol was able to counteract all corticosterone-induced effects. One of the main kinases involved in tau phosphorylation, glycogen synthase kinase 3β (GSK3β), which is inactivated by phosphorylation by pAkt, was found to be decreased after corticosterone and increased after propranolol treatment. Concomitant changes in pTau expression were found. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for pathologies associated with the interaction glucocorticoids-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.

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