Alzheimers: The Disease of the Century

Alzheimer's disease is the major cause of dementia in the United States, with spending in the range of $100 billion annually. It affects 5 to 7 percent of people over 65 years of age and 20 to 40 percent over 80, and is estimated to be the fourth to fifth most common cause of death in the United States. Concerted research efforts in the clinical and basic neurosciences in the last 30 years have resulted in marked advances in our understanding of the clinical course and mechanisms of Alzheimer's disease as well as new therapeutic directions. This review provides a short history of the progress that has been made in Alzheimer's disease research during this time, and identifies some of the seminal discoveries and insights that contributed to this progress

Selective remodeling of cardiolipin fatty acids in the aged rat heart

BACKGROUND: The heart is rich in cardiolipin, a phospholipid acylated in four sites, predominately with linoleic acid. Whether or not aging alters the composition of cardiolipin acyl chains is controversial. We therefore measured the fatty acid concentration of cardiolipin in hearts of 4, 12 and 24 month old rats that consumed one diet, adequate in fatty acids for the duration of their life. RESULTS: The concentration (nmol/g) of linoleic acid was decreased in 24 month old rats (3965 ± 617, mean ± SD) vs 4 month old rats (5525 ± 656), while the concentrations of arachidonic and docosahexaenoic acid were increased in 24 month old rats (79 ± 9 vs 178 ± 27 and 104 ± 16 vs 307 ± 68 for arachidonic and docosahexaenoic acids, 4 months vs 24 months, respectively). Similar changes were not observed in ethanolamine glycerophospholipids or plasma unesterified fatty acids, suggesting specificity of these effects to cardiolipin. CONCLUSION: These results demonstrate that cardiolipin remodeling occurs with aging, specifically an increase in highly unsaturated fatty acids

Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: Relevance to valproate's efficacy against bipolar disorder

Background—The ability of chronic valproate (VPA) to reduce arachidonic acid (AA) turnover in brain phospholipids of unanesthetized rats has been ascribed to its inhibition of acyl-CoA synthetase (Acsl)-mediated activation of AA to AA-CoA. Our aim was to identify a rat Acsl isoenzyme that could be inhibited by VPA in vitro. Methods—Rat Acsl3-, Acsl6v1- and Acsl6v2-, and Acsl4-flag proteins were expressed in E. coli, and the ability of VPA to inhibit their activation of long-chain fatty acids to acyl-CoA was estimated using Michaelis-Menten kinetics. Results—VPA uncompetitively inhibited Acsl4-mediated conversion of AA and of docosahexaenoic (DHA) but not of palmitic acid to acyl-CoA, but did not affect AA conversion by Acsl3, Acsl6v1 or Acsl6v2. Acsl4-mediated conversion of AA to AA-CoA showed substrate inhibition and had a 10-times higher catalytic efficiency than did conversion of DHA to DHACoA. Butyrate, octanoate, or lithium did not inhibit AA activation by Acsl4. Conclusions—VPA’s ability to inhibit Acsl4 activation of AA and of DHA to their respective acyl-CoAs, related to the higher catalytic efficiency of AA than DHA conversion, may account for VPA’s selective reduction of AA turnover in rat brain phospholipids, and contribute to VPA’s efficacy against bipolar disorder

Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega‐3 plasma concentrations are altered by treatment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115916/1/bdi12337_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115916/2/bdi12337.pd

Neuropathological Responses to Chronic NMDA in Rats Are Worsened by Dietary n-3 PUFA Deprivation but Are Not Ameliorated by Fish Oil Supplementation

Background Dietary long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation may be beneficial for chronic brain illnesses, but the issue is not agreed on. We examined effects of dietary n-3 PUFA deprivation or supplementation, compared with an n-3 PUFA adequate diet (containing alpha-linolenic acid [18:3 n-3] but not docosahexaenoic acid [DHA, 22:6n-3]), on brain markers of lipid metabolism and excitotoxicity, in rats treated chronically with NMDA or saline. Methods Male rats after weaning were maintained on one of three diets for 15 weeks. After 12 weeks, each diet group was injected i.p. daily with saline (1 ml/kg) or a subconvulsive dose of NMDA (25 mg/kg) for 3 additional weeks. Then, brain fatty acid concentrations and various markers of excitotoxicity and fatty acid metabolism were measured. Results Compared to the diet-adequate group, brain DHA concentration was reduced, while n-6 docosapentaenoic acid (DPA, 22:5n-6) concentration was increased in the n-3 deficient group; arachidonic acid (AA, 20:4n-6) concentration was unchanged. These concentrations were unaffected by fish oil supplementation. Chronic NMDA increased brain cPLA2 activity in each of the three groups, but n-3 PUFA deprivation or fish oil did not change cPLA2 activity or protein compared with the adequate group. sPLA2 expression was unchanged in the three conditions, whereas iPLA2 expression was reduced by deprivation but not changed by supplementation. BDNF protein was reduced by NMDA in N-3 PUFA deficient rats, but protein levels of IL-1β, NGF, and GFAP did not differ between groups. Conclusions N-3 PUFA deprivation significantly worsened several pathological NMDA-induced changes produced in diet adequate rats, whereas n-3 PUFA supplementation did not affect NMDA induced changes. Supplementation may not be critical for this measured neuropathology once the diet has an adequate n-3 PUFA content

Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats

Correction to Rao J S, Kim H W, Kellom M, Greenstein D, Chen M, Kraft A D, Harry G J, Rapoport S I, Basselin M. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats. Journal of Neuroinflammation 8:101