Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice.

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.

Pine Bark Polyphenolic Extract Attenuates Amyloid-ß and Tau Misfolding in a Model System of Alzheimer's Disease Neuropathology.

Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer's disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-ß protein (Aß). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aß1-40 and Aß1-42, but also tau in vitro. Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O-ß-Glucuronide, Me-(±)-C-O-ß-glucuronide, EC-O-ß-glucuronide, and (±)-C-O-ß-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD.

Oleanane triterpenoids from Akebiae Caulis exhibit inhibitory effects on Aß42 induced fibrillogenesis.

Previous phytochemical investigations of Akebiae Caulis resulted in the isolation of triterpenes, triterpene glycosides, phenylethanoid glycosides and megastigmane glycoside. Amyloid beta (Aß), the main component of the senile plaques detected in Alzheimer's disease, induces cell death. However, only a limited number of studies have addressed the biological and pharmacological effects of Akebiae Caulis. In particular, the inhibitory activity of Akebiae Caulis against Aß42 fibrillogenesis remains unclear. Herein, a new triterpene glycoside, akequintoside F (1), along with nine known compounds pulsatilla saponin A (2), collinsonidin (3), akebonic acid (4), hederagenin (5), 1-(3',4'-dihydroxycinnamoyl) cyclopentane-2,3-diol (6), asperosaponin C (7), leontoside A (8), quinatic acid (9), and quinatoside A (10) were isolated from Akebiae Caulis using repeated column chromatography with silica gel, LiChroprep RP-18, and MCI gel. The chemical structures of compounds 1-10 were illustrated based on 1D and 2D NMR spectroscopy, including 1H-1H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Compound 1 a novel compound and known compounds 6 and 7 were isolated for the first time from this plant. Among these compounds, 1, 3, 4, 5 and 7 displayed significant inhibitory effects on Aß42 induced fibrillogenesis. We present the first report of new compound 1 and the inhibitory effects of components from Akebiae Caulis on Aß42 fibrillogenesis.

Activation of the unfolded protein response and granulovacuolar degeneration are not common features of human prion pathology.

Human prion diseases are fatal neurodegenerative disorders with a genetic, sporadic or infectiously acquired aetiology. Neuropathologically, human prion diseases are characterized by deposition of misfolded prion protein and neuronal loss. In post-mortem brain tissue from patients with other neurodegenerative diseases characterized by protein misfolding, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology (FTLD-tau), increased activation of the unfolded protein response (UPR) has been observed. The UPR is a cellular stress response that copes with the presence of misfolded proteins. Recent studies have indicated that UPR activation is also involved in experimental models of prion disease and have suggested intervention in the UPR as a therapeutic strategy. On the other hand, it was previously shown that the active form of the UPR stress sensor dsRNA-activated protein kinase-like ER kinase (PERK) is not increased in post-mortem brain tissue samples from human prion disease cases. In the present study, we assessed the active form of another UPR stress sensor, inositol-requiring enzyme 1α (IRE1α), in human post-mortem frontal cortex of a large cohort of sporadic, inherited and acquired prion disease patients (n = 47) and non-neurological controls. Immunoreactivity for phosphorylated IRE1α was not increased in prion disease cases compared with non-neurological controls. In addition, immunoreactivity for phosphorylated PERK was unaltered in human prion disease cases included in the current cohort. Moreover, no difference in the extent of granulovacuolar degeneration, a pathological feature associated with the presence of UPR activation markers, was detected. Our data indicate that, in contrast to AD and primary tauopathies, activation of the UPR is not a common feature of human prion pathology.

Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, α-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease.

Brain tocopherols related to Alzheimer's disease neuropathology in humans.

Randomized trials of α-tocopherol supplements on cognitive decline are negative, whereas studies of dietary tocopherols have shown benefit. We investigated these inconsistencies by analyzing the relations of α- and γ-tocopherol brain concentrations to Alzheimer's disease (AD) neuropathology among 115 deceased participants of the prospective Rush Memory and Aging Project. Associations of amyloid load and neurofibrillary tangle severity with brain tocopherol concentrations were examined in separate adjusted linear regression models. γ-Tocopherol concentrations were associated with lower amyloid load (ß = -2.10, P = .002) and lower neurofibrillary tangle severity (ß = -1.16, P = .02). Concentrations of α-tocopherol were not associated with AD neuropathology, except as modified by γ-tocopherol: high α-tocopherol was associated with higher amyloid load when γ-tocopherol levels were low and with lower amyloid levels when γ-tocopherol levels were high (P for interaction = 0.03). Brain concentrations of γ- and α-tocopherols may be associated with AD neuropathology in interrelated, complex ways. Randomized trials should consider the contribution of γ-tocopherol.

Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aß amyloidosis.

Histopathological studies on the brains of tauopathy cases including cases with Alzheimer's disease (AD) demonstrate that neurons with hyperphosphorylated protein tau display granulovacuolar degeneration (GVD), as evidenced by vacuolar lesions harboring a central granule, together with markers of the activated unfolded protein response (UPR). In order to examine whether this hallmark is reproduced in animal models we studied the presence of GVD and the activated UPR in two complementary mouse models, pR5 mice with a tau pathology and APPSLxPS1mut mice with an amyloid plaque pathology. Neither GVD nor a significant activation of the UPR was found in both APPSLxPS1mut mice and in those regions in the pR5 brain where only neurons with an early stage of tau hyperphosphorylation were present. In contrast, those neurons that displayed a tau phospho-epitope signature that only appeared in old pR5 mice and also correlated with Gallyas-positive tangle staining harbored granulovacuolar lesions that were labeled with the GVD markers casein kinases 1δ and 1ε. Granulovacuolar lesions in pR5 mice were also labeled with the UPR markers phosphorylated PKR-like endoplasmic reticulum kinase, phosphorylated inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α. However, GVD was rarely observed in neurons bearing mature neurofibrillary tangles as evidenced by Congo red staining. Our results suggest that NFT-formation activates the UPR in pR5 mice and that it is the early stages of neurofibrillary tangle formation that are accompanied by GVD, in line with observations from studies on human autopsy cases.

Protein aggregation and prionopathies.

Prion protein and prion-like proteins share a number of characteristics. From the molecular point of view, they are constitutive proteins that aggregate following conformational changes into insoluble particles. These particles escape the cellular clearance machinery and amplify by recruiting the soluble for of their constituting proteins. The resulting protein aggregates are responsible for a number of neurodegenerative diseases such as Creutzfeldt-Jacob, Alzheimer, Parkinson and Huntington diseases. In addition, there are increasing evidences supporting the inter-cellular trafficking of these aggregates, meaning that they are "transmissible" between cells. There are also evidences that brain homogenates from individuals developing Alzheimer and Parkinson diseases propagate the disease in recipient model animals in a manner similar to brain extracts of patients developing Creutzfeldt-Jacob's disease. Thus, the propagation of protein aggregates from cell to cell may be a generic phenomenon that contributes to the evolution of neurodegenerative diseases, which has important consequences on human health issues. Moreover, although the distribution of protein aggregates is characteristic for each disease, new evidences indicate the possibility of overlaps and crosstalk between the different disorders. Despite the increasing evidences that support prion or prion-like propagation of protein aggregates, there are many unanswered questions regarding the mechanisms of toxicity and this is a field of intensive research nowadays.

Vaccination with Sarkosyl insoluble PHF-tau decrease neurofibrillary tangles formation in aged tau transgenic mouse model: a pilot study.

Active immunization using tau phospho-peptides in tauopathy mouse models has been observed to reduce tau pathology, especially when given prior to the onset of pathology. Since tau aggregates in these models and in human tauopathies are composed of full-length tau with many post-translational modifications, and are composed of several tau isoforms in many of them, pathological tau proteins bearing all these post-translational modifications might prove to be optimal tau conformers to use as immunogens, especially in models with advanced tau pathology. To this aim, we immunized aged wild-type and mutant tau mice with preparations containing human paired helical filaments (PHF) emulsified in Alum-adjuvant. This immunization protocol with fibrillar PHF-tau was well tolerated and did not induce an inflammatory reaction in the brain or adverse effect in these aged mice. Mice immunized with four repeated injections developed anti-PHF-tau antibodies with rising titers that labeled human neurofibrillary tangles in situ. Immunized mutant tau mice had a lower density of hippocampal Gallyas-positive neurons. Brain levels of Sarkosyl-insoluble tau were also reduced in immunized mice. These results indicate that an immunization protocol using fibrillar PHF-tau proteins is an efficient and tolerated approach to reduce tau pathology in an aged tauopathy animal model.

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer's disease (3xTgAD) mice.

Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No ß-amyloid (Aß) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

[Muro disease: amyotrophic lateral sclerosis/parkinsonism-dementia complex in Kii peninsula of Japan].

Muro disease refers to the endemic amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in the high incidence ALS focus in the Muro district of the Kii peninsula. Kii paralysis was first described in the 1680s in a folk literature, and as ALS in the medical literature by Kin-no-suke Miura in 1911. Two high-incidence ALS foci were discovered in 1960s by Kimura and Yase, and retro- and anterospective epidemiological surveys were started. Kii ALS was neuropathologically characterized by classical ALS pathology together with many neurofibrillary tangles (NFTs) in the brain, similar to Guamanian ALS. The incidence rates of ALS dramatically declined during the 1950s and 1980s, resulting in the disappearance of the high-incidence foci. In the early 1990s, however, Kuzuhara found existence of high-incidence of ALS in the region, and, in addition, of a high-incidence of PDC with abundant NFTs, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced ALS. Unsuccessful attempts were made to identify cause and pathogenesis of the disease in minerals and environmental factors. More than 70% of patients in the endemic region had a family history of ALS or PDC; therefore, genetic factors were suspected as the cause. The authors analyzed the causative and risk candidate genes in the affected and unaffected family members, but failed to find genes related to ALS/PDC. The changing pattern of Muro disease from ALS with a younger onset and rapid progression to PDC with a later onset and longer survival suggests that some unknown environmental factor(s) might modulate the disease process, which basically might be programmed in the gene(s).

Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer's disease.

Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti-phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain.

Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic neurodegenerative tau pathologies.

Annonacin, a natural lipophilic inhibitor of mitochondrial complex I has been implicated in the etiology of a sporadic neurodegenerative tauopathy in Guadeloupe. We therefore studied further compounds representing the broad biochemical spectrum of complex I inhibitors to which humans are potentially exposed. We determined their lipophilicity, their effect on complex I activity in submitochondrial particles, and their effect on cellular ATP levels, neuronal cell death and somatodendritic redistribution of phosphorylated tau protein (AD2 antibody against pS396/pS404-tau) in primary cultures of fetal rat striatum. The 24 compounds tested were lipophilic (logP range 0.9-8.5; exception: MPP(+) logP=-1.35) and potent complex I inhibitors (IC(50) range 0.9 nM-2.6 mM). They all decreased ATP levels (EC(50) range 1.9 nM-54.2 microM), induced neuronal cell death (EC(50) range 1.1 nM-54.5 microM) and caused the redistribution of AD2(+) tau from axons to the cell body (EC(5) range 0.6 nM-33.3 microM). The potency of the compounds to inhibit complex I correlated with their potency to induce tau redistribution (r=0.80, p<0.001). In conclusion, we propose that the widely distributed lipophilic complex I inhibitors studied here might be implicated in the induction of tauopathies with global prevalence.

Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging.

BACKGROUND AND PURPOSE: Most of the neuropathological studies in brain aging were based on the assumption of a symmetrical right-left hemisphere distribution of both Alzheimer disease and vascular pathology. To explore the impact of asymmetrical lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle and Ass deposition staging, microvascular pathology, and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and Clinical Dementia Rating scores was assessed using ordered logistic regression. RESULTS: Unlike Braak neurofibrillary tangle and Ass deposition staging, vascular scores were significantly higher in the left hemisphere for all Clinical Dementia Rating scores. A negative relationship was found between Braak neurofibrillary tangle, but not Ass staging, and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak neurofibrillary tangle staging was the main determinant of cognitive decline followed by vascular scores and Ass deposition staging. The concomitant predominance of Alzheimer disease and vascular pathology in the right hemisphere was associated with significantly higher Clinical Dementia Rating scores. CONCLUSIONS: Our data show that the cognitive impact of Alzheimer disease and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and Alzheimer disease burden in the right hemisphere may increase the risk for dementia in this group.

[The lesions of Alzheimer's disease: which therapeutic perspectives?]. / "La maladie d'Alzheimer, Les lésions de la maladie d'Alzheimer. Perspectives thérapeutiques?

The brain lesions associated with Alzheimer's disease are caused by extracellular accumulation of Abeta peptide and intracellular accumulation of tau protein. Abeta peptide makes the core of the senile plaque (the "focal deposit"); it is also present in the extracellular "diffuse deposits" and in the vessel walls. Neurofibrillary tangles, and neuropil threads are composed of hyperphosphorylated tau that also accumulates in the processes of the corona of the senile plaque. The Abeta deposits first involve the neocortex, while the tau pathology is initially found in the hippocampal region. Abeta deposits first occur in the neocortex, while intracellular tau accumulation mainly affect the hippocampal region. Abeta peptide deposits are initially found in all the neocortical areas, then involve the hippocampus and the subcortical nuclei. Tau lesions successively involve the hippocampal regions, multi- and uni-modal areas and finally the primary cortices in stereotyped stages. Mutations of APP, the precursor of Abeta peptide, cause autosomal dominant familial Alzheimer disease, suggesting that a cascade of reactions link Abeta overproduction, tau pathology and the clinical phenotype. Transgenic mice bearing the mutated human APP gene (APP mice) develop A deposits. Systemic injection of Abeta peptide prevents the deposition of Abeta peptide. However, a clinical trial had to be interrupted when meningoencephalitis occurred in a significant proportion of treated patients. Post mortem studies showed a relative scarcity of Abeta deposits. Forthcoming immunotherapy studies should soon show whether the prevention of Abeta deposition interrupts disease progression.

Transducible P11-CNTF rescues the learning and memory impairments induced by amyloid-beta peptide in mice.

Alzheimer's disease is a progressive brain disorder with the loss of memory and other intellectual abilities. Amyloid species and neurofibrillary tangles are the prime suspects in damaging and killing nerve cells. Abnormal accumulation of Amyloid-beta peptide (Abeta) may cause synaptic dysfunction and degeneration of neurons. Drugs that can prevent its formation and accumulation or stimulate its clearance might ultimately be of therapeutic benefit. Ciliary neurotrophic factor (CNTF), a neurotrophic cytokine, promotes the survival of various neurons in brain. However, the blood-brain barrier hinders the systemic delivery of CNTF to brain. Recently the 11-amino acid of protein transduction domain TAT has successfully assisted the delivery of many macromolecules to treat preclinical models of human disease. The present study aimed to evaluate whether P11-CNTF fusion protein (P11-CNTF) is protective against the Abeta25-35-induced dementia in mice. Immunofluorescence experiments showed that P11 effectively carried CNTF to the SH-SY5Y cells in vitro, and to the brains of mice in vivo. The learning and memory impairments of mice induced by Abeta were substantially rescued by supplement with the P11-CNTF. Furthermore, mRNAs of enzymes involved in the Abeta metabolism, e.g. neprilysin (NEP), endothelin-converting enzyme 1 (ECE-1) and insulin degrading enzyme (IDE), increased in the P11-CNTF treated dementia mice, accompanied by the proliferation of nestin- and choline acetyltransferase (ChAT)-positive cells in hippocampus. It implies that the delivery of P11-CNTF may be a novel treatment for Alzheimer's disease.

Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1's attenuation of beta-amyloid peptide25-35-induced tau hyperphosphorylation in cortical neurons.

Increasing evidence have shown that beta-amyloid (Abeta) induced hyperphosphorylation of tau, which eventually resulted in the disruption of microtubule (MT) integrity. Cyclin-dependent kinase 5 (CDK5) and its activator p35 are required for neurite outgrowth. The cleavage of p35 to p25, mediated by calpain and calcium, caused CDK5 dislocation and subsequently p25/CDK5-induced tau hyperphosphorylation, which disrupted the cytoskeleton and resulted in neuronal death. In the present study we investigated the effects of ginsenoside Rb1 on fibrillar Abeta(25-35)-induced tau hyperphosphorylation in primary cultured cortical neurons and also the potential involvement of Ca(2+)-calpain-CDK5 signal pathway. The present study suggests that Ca(2+), calpain, and p25 in CDK5 pathway may play important roles in Abeta(25-35)-induced tau hyperphosphorylation.

Docosahexaenoic acid protects from amyloid and dendritic pathology in an Alzheimer's disease mouse model.

Genetic data argues that Alzheimer's disease (AD) can be initiated by aggregates of a 42 amino acid beta amyloid peptide (Abeta42). The Abeta aggregates, notably small oligomer species, cause a cascade of events including oxidative damage, inflammation, synaptic toxicity and accumulation of intraneuronal inclusions; notably neurofibrillary tangles. Cognitive deficits are likely to begin with a failure of synaptogenesis and synaptic plasticity with dendritic spine loss and dying back of dendritic arbor. This is followed by neuron loss in key areas involved in learning and memory. Significant prevention or delay of clinical onset may be achievable by modifying environmental risk factors that impact the underlying pathogenic pathways. Because low fish intake and low blood levels of the marine lipid, docosahexaenoic acid (DHA) have been associated with increased AD risk we have tested the impact of depleting or supplementing with dietary DHA on AD pathogenesis in transgenic mice bearing a mutant human gene known to cause AD in people. We reported that even with intervention late in life dietary DHA depletion dramatically enhanced oxidative damage and the loss of dendritic markers, while DHA supplementation markedly reduced Abeta42 accumulation and oxidative damage, corrected many synaptic deficits and improved cognitive function. Loss of brain DHA was exacerbated in mice expressing the mutant human AD transgene, this is consistent with evidence for increased oxidative attack on DHA oxidation in AD. Treatment with the curry spice extract curcumin, a polyphenolic antioxidant that inhibits AP aggregation, has been strongly protective in the same mouse model. Many Western diets are typically deficient in DHA and low in polyphenolic antioxidant intake. These and other data argue that increasing dietary intake of both DHA and polyphenolic antioxidants may be useful for AD prevention.

Nuclear pore complex proteins in Alzheimer disease.

Ultrastructural studies of neurofibrillary tangles in Alzheimer disease (AD) have demonstrated a close relationship between nuclear pores and the cytoplasmic paired helical filaments comprising the tangles, as well as nuclear irregularity in many tangle-bearing neurons; nuclear pore aggregation has been observed in nearby neurons. These observations prompted examination of the nuclear pore complex (NPC) and proteins critical to nucleocytoplasmic transport in neurons with and without tangles in AD and control cases. Light microscopic study of hippocampus and neocortex in AD and controls revealed that all nuclei were labeled by antibodies to NPC proteins, including the central transporter nucleoporin Nup62. Nucleoporin and tau label revealed significantly more nuclear irregularity in AD, often associated with neurofibrillary tangles. Double label of Nup62 with apoptotic markers (TUNEL and active caspase-3) and a cell-cycle protein (cyclin B1) revealed no clear relationship of nuclear irregularity to apoptosis or cell-cycle protein expression. However, cytoplasmic accumulation of nuclear transport factor 2 (NTF2), a protein that transports cargo from the cytoplasm into the nucleus, was observed in a subset of hippocampal neurons with and without tangles in AD but not control cases. Further investigation of the NPC and nucleocytoplasmic transport in AD is warranted.