Journal of Alzheimer's Disease - Volume 30, issue s2

Authors: Farooqui, Akhlaq A.

Article Type: Review Article

Abstract: Lipid mediators are important endogenous regulators derived from enzymatic degradation of glycerophospholipids, sphingolipids, and cholesterol by phospholipases, sphingomyelinases, and cytochrome P450 hydroxylases, respectively. In neural cells, lipid mediators are associated with proliferation, differentiation, oxidative stress, inflammation, and apoptosis. A major group of lipid mediators, which originates from the enzymatic oxidation of arachidonic acid, is called eicosanoids (i.e., prostaglandins, leukotrienes, thromboxanes, and lipoxins). The corresponding lipid mediators of docosahexaenoic acid metabolism are named as docosanoids. They include resolvins, protectins (neuroprotectins), and maresins. Docosanoids produce antioxidant, anti-inflammatory, and antiapoptotic effects in brain tissue. Other glycerophospholipid-derived lipid mediators are platelet activating factor, lysophosphatidic …acid, and endocannabinoids. Degradation of sphingolipids also results in the generation of sphingolipid-derived lipid mediators, such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These mediators are involved in differentiation, growth, cell migration, and apoptosis. Similarly, cholesterol-derived lipid mediators, hydroxycholesterol, produce apoptosis. Abnormal metabolism of lipid mediators may be closely associated with pathogenesis of Alzheimer's disease. Show more

Keywords: Ceramide, ceramide 1-phosphate, docosanoids, eicosanoids, hydroxycholesterol, platelet activating factor, sphingosine 1-phosphate

DOI: 10.3233/JAD-2011-111085

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S163-S178, 2012

Authors: Little, Jonathan P. | Madeira, Jocelyn M. | Klegeris, Andis

Article Type: Research Article

Abstract: Obesity is linked to increased risk of Alzheimer's disease and cognitive impairment. Microglia-mediated neuroinflammation is implicated in neuronal loss. Elevated levels of fatty acids seen in obesity induce inflammation in peripheral tissues. Whether fatty acids promote neuroinflammation is unknown. Using an established neuroinflammation model involving human microglia-like THP-1 cells and SH-SY5Y neuroblastoma cells, we show that the saturated fatty acid palmitate, but not the unsaturated fatty acids oleate or linoleate, induces THP-1 cell pro-inflammatory cytokine secretion and neurotoxicity. Inhibition of c-Jun NH2 -terminal kinase (JNK) reduces this neurotoxicity. Therefore, elevated saturated fatty acids may induce neuroinflammation through pathways involving JNK …activation. Show more

Keywords: Alzheimer's disease, metabolic syndrome X, microglia, neurodegeneration, palmitic acid

DOI: 10.3233/JAD-2011-111262

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S179-S183, 2012

Authors: Luchsinger, José A.

Article Type: Review Article

Abstract: This manuscript provides a brief review of current concepts in the mechanisms potentially linking type-2-diabetes (T2D) with cognitive impairment. Existing epidemiologic studies, imaging studies, autopsy studies, and clinical trials provide insights into the mechanisms linking T2D and cognitive impairment. There seems to be little dispute that T2D can cause cerebrovascular disease and thus cause vascular cognitive impairment (VCI). Whether T2D can cause late onset Alzheimer's disease (LOAD) remains to be elucidated. Many epidemiologic studies show an association between T2D and cognitive impairment, but the association with VCI seems to be stronger compared to LOAD, suggesting that cerebrovascular disease may be …the main mechanism linking T2D and cognitive impairment. Imaging studies show an association between T2D and imaging markers of LOAD, but these observations could still be explained by cerebrovascular mechanisms. Autopsy studies are few and conflicting, with some suggesting a predominantly cerebrovascular mechanism, and others providing support for a neurodegenerative mechanism. Thus far, the evidence from clinical trials is mixed in supporting a causal association between T2D and cognitive impairment, and most clinical trials that can answer this question are yet to be reported or finished. Given the epidemic of T2D in the world, it is important to elucidate whether the association between T2D and cognitive impairment, particularly LOAD, is causal, and if so, what the mechanisms are. Show more

Keywords: Dementia, late onset Alzheimer's disease, mechanisms, Type 2 diabetes, vascular cognitive impairment

DOI: 10.3233/JAD-2012-111433

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S185-S198, 2012

Authors: Moreira, Paula I.

Article Type: Review Article

Abstract: An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and …diabetes is needed for the design of effective preventive and therapeutic strategies. Show more

Keywords: Alzheimer's disease, diabetes, insulin signaling impairment, mitochondrial abnormalities, oxidative stress

DOI: 10.3233/JAD-2011-111127

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S199-S215, 2012

Authors: de la Monte, Suzanne M. | Re, Edward | Longato, Lisa | Tong, Ming

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), brain insulin and insulin-like growth factor (IGF) resistance and deficiency begin early, and worsen with severity of disease. The factors mediating progression of brain insulin/IGF resistance in AD are not well understood. We hypothesize that AD progression is mediated via negative cross-talk that promotes toxic ceramide generation and endoplasmic reticulum (ER) stress. The rationale is that insulin resistance dysregulates lipid metabolism and promotes ceramide accumulation, and thereby increases inflammation and stress. Consequences include disruption of cytoskeletal function and AβPP-Aβ secretion. The present study correlates AD stage with activation of pro-ceramide genes, ceramide levels, and molecular indices …of ER stress in postmortem human brain tissue. The results demonstrated that in AD, brain insulin/IGF resistance was associated with constitutive activation of multiple pro-ceramide genes, increased ceramide levels, and increased expression of pro-ER stress pathway genes and proteins. Expression of several pro-ceramide and pro-apoptotic ER stress pathway molecules increased with AD severity and brain insulin/IGF resistance. In contrast, ER stress molecules that help maintain homeostasis with respect to unfolded protein responses were mainly upregulated in the intermediate rather than late stage of AD. These findings support our hypothesis that in AD, a triangulated mal-signaling network initiated by brain insulin/IGF resistance is propagated by the dysregulation of ceramide and ER stress homeostasis, which themselves promote insulin resistance. Therefore, once established, this reverberating loop must be targeted using multi-pronged approaches to disrupt the AD neurodegeneration cascade. Show more

Keywords: Alzheimer's disease, central nervous system, ceramide, ER stress, human, insulin resistance, neurodegeneration, neurons, postmortem brain

DOI: 10.3233/JAD-2012-111728

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S217-S229, 2012

Authors: de la Monte, Suzanne M.

Article Type: Review Article

Abstract: Ceramides are lipid signaling molecules that cause cytotoxicity and cell death mediated by insulin resistance, inflammation, and endoplasmic reticulum (ER) stress. However, insulin resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and ER stress. Herein, we discuss two major pathways, extrinsic and intrinsic, that converge and often overlap in propagating AD-type neurodegeneration via a triangulated mal-signaling network. First, we review evidence that systemic insulin resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues (e.g., liver) get released into peripheral blood, and subsequently transit …across the blood-brain barrier into the brain where they induce brain insulin resistance, inflammation, and cell death (extrinsic pathway). Then we discuss the role of the intrinsic pathway of neurodegeneration which is mediated by endogenous or primary brain insulin/IGF resistance, and impairs neuronal and oligodendrocyte survival, energy metabolism, membrane integrity, cytoskeletal function, and AβPP-Aβ secretion. The end result is increased ER stress and ceramide generation, which exacerbate brain insulin resistance, cell death, myelin degeneration, and neuroinflammation. Altogether, the data suggest that the triangulated mal-signaling network mediated by toxic ceramides, ER stress, and insulin resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade. Show more

Keywords: Central nervous system, ceramide, diabetes mellitus, insulin resistance, myelin, neurodegeneration, neurons, non-alcoholic steatohepatitis, oligodendrocytes

DOI: 10.3233/JAD-2012-111727

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S231-S249, 2012

Authors: Kehoe, Patrick G. | Passmore, Peter A.

Article Type: Review Article

Abstract: There is an urgent need to improve upon Alzheimer's disease (AD) treatments. Limitations of existing drugs are that they target specific downstream neurochemical abnormalities while the upstream underlying pathology continues unchecked. Preferable treatments would be those that can target a number of the broad range of molecular and cellular abnormalities that occur in AD such as amyloid-β (Aβ) and hyperphosphorylated tau-mediated damage, inflammation, and mitochondrial dysfunction, as well more systemic abnormalities such as brain atrophy, impaired cerebral blood flow (CBF), and cerebrovascular disease. Recent pre-clinical, epidemiological, and a limited number of clinical investigations have shown that prevention of the signaling …of the multifunctional and potent vasoconstrictor angiotensin II (Ang II) may offer broad benefits in AD. In addition to helping to ameliorate co-morbid hypertension, these drugs also likely improve diminished CBF which is common in AD and can contribute to focal Aβ pathology. These drugs, angiotensin converting enzyme (ACE) inhibitors, or angiotensin receptor antagonists (ARAs) may also help deteriorating cognitive function by preventing Ang II-mediated inhibition of acetylcholine release as well as interrupt the upregulation of deleterious inflammatory pathways that are widely recognized in AD. Given the current urgency to find better treatments for AD and the relatively immediate availability of drugs that are already widely prescribed for the treatment of hypertension, one of the largest modifiable risk factors for AD, this article reviews current knowledge as to the eligibility of ACE-inhibitors and ARAs for consideration in future clinical trials in AD. Show more

Keywords: Acetylcholine, Alzheimer's disease, amyloid-β, amyloid-β protein precursor, angiotensin, antagonist, cognitive decline, degradation, dementia, hypertension, treatment, vascular

DOI: 10.3233/JAD-2012-111376

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S251-S268, 2012

Authors: Goodison, William V. | Frisardi, Vincenza | Kehoe, Patrick G.

Article Type: Review Article

Abstract: Midlife hypertension is a risk factor for late onset Alzheimer's disease (AD) and it is one of the components of metabolic syndrome (MetS). Observational studies and some cardiovascular disease-related clinical trials suggest that antihypertensive treatment reduced the incidence and progression of AD. Calcium channel blockers (CCBs), one of the more commonly used treatments for hypertension, target voltage-gated calcium channels (VGCCs) which are found on neurons in the brain where calcium regulation is very important in both learning and memory. Amyloid-β (Aβ) peptide, one of the main pathological hallmarks of AD, causes increases to intracellular calcium via VGCCs, which in turn …leads to further increases in Aβ production. Memantine, a current treatment used in AD, exerts some of its beneficial effects by blocking calcium entry into neurons. We explore the possibility of whether CCBs acting in the brain may delay the onset and progression of AD and thus may inform treatment regimes in people with MetS. Show more

Keywords: Alzheimer's disease, amyloid-β, blood brain barrier, calcium, calcium channel blocker, cognitive decline, dementia, hypertension, metabolic syndrome, treatment, voltage-gated calcium channel

DOI: 10.3233/JAD-2012-111664

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S269-S282, 2012

Authors: Frisardi, Vincenza

Article Type: Review Article

Abstract: Apolipoprotein E [ApoE, APOE (gene)] is a multifunctional protein of the lipid and lipoprotein transport system mainly involved in metabolism of dietary lipids. Its polymorphic variants are considered a genetic risk factor of cognitive impairment in several neurodegenerative disorders such as Lewy body dementia, Huntington's disease, and Alzheimer's disease, as well as in vascular dementia and cerebrovascular disease. The precise mechanism by which APOE affects neurodegeneration is still unclear. Epidemiological and experimental studies demonstrated an influence of APOE on metabolic parameters but, to the best of our knowledge, no data are available about the exact role in humans of the …effect of APOE on metabolic-cognitive syndrome (MCS). The latter is a model of cognitive impairment linked to metabolic syndrome identifying a grey zone between metabolic disorders and neuropathological process driving late-life cognitive decline. Although it may be a daring project that does not reach a final conclusion because of disease complexity, I hope to elucidate whether APOE may have a prominent role in MCS, going beyond the simple addition of separate mechanisms already known. Show more

Keywords: Apolipoprotein E isoforms, metabolic syndrome, neurodegenerative disorders, vascular-related factors

DOI: 10.3233/JAD-2012-111568

Citation: Journal of Alzheimer's Disease, vol. 30, no. s2, pp. S283-S304, 2012