Mari Takalo

Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition ☆

Dietary fish oil, providing n3 polyunsaturated fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), associates with reduced dementia risk in epidemiological studies and reduced amyloid accumulation in Alzheimer mouse models. We now studied whether additional nutrients can improve the efficacy of fish oil in alleviating cognitive deficits and amyloid pathology in APPswe/PS1dE9 transgenic and wild-type mice. We compared four isocaloric (5% fat) diets. The fish oil diet differed from the control diet only by substituted fish oil. Besides fish oil, the plant sterol diet was supplemented with phytosterols, while the Fortasyn diet contained as supplements precursors and cofactors for membrane synthesis, viz. uridine-monophosphate; DHA and EPA; choline; folate; vitamins B6, B12, C and E; phospholipids and selenium. Mice began the special diets at 5 months and were sacrificed at 14 months after behavioral testing. Transgenic mice, fed with control chow, showed poor spatial learning, hyperactivity in exploring a novel cage and reduced preference to explore novel odors. All fish-oil-containing diets increased exploration of a novel odor over a familiar one. Only the Fortasyn diet alleviated the spatial learning deficit. None of the diets influenced hyperactivity in a new environment. Fish-oil-containing diets strongly inhibited β- and γ-secretase activity, and the plant sterol diet additionally reduced amyloid-β 1-42 levels. These data indicate that beneficial effects of fish oil on cognition in Alzheimer model mice can be enhanced by adding other specific nutrients, but this effect is not necessarily mediated via reduction of amyloid accumulation.

High-fat diet increases tau expression in the brain of T2DM and AD mice independently of peripheral metabolic status.

Alzheimers disease and type 2 diabetes mellitus are risk factors for each other. To investigate the effects of both genetic and high-fat-induced diabetic phenotype on the expression and exon 10 splicing of tau, we used the Alzheimers disease mouse model (APdE9) cross-bred with the type 2 diabetes mouse model over-expressing insulin-like growth factor 2 in the pancreas. High-fat diet, regardless of the genotype, significantly induced the expression of four repeat tau mRNA and protein in the temporal cortex of female mice. The mRNA levels of three repeat tau were also significantly increased by high-fat diet in the temporal cortex, although three repeat tau expression was considerably lower as compared to four repeat tau. Moreover, high-fat diet significantly increased the mRNA ratio of four repeat tau vs. three repeat tau in the temporal cortex of these mice. All of these effects were independent of the peripheral hyperglycemia, hyperinsulinemia and insulin resistance. Increased four repeat tau and three repeat tau levels significantly associated with impaired memory and reduced rearing in the female mice. High-fat diet did not affect neuroinflammation, Akt/GSK3β signaling pathway or the expression of tau exon 10 splicing enhancers in the temporal cortex. Our study suggests that the high-fat diet independently of type 2 diabetes or Alzheimers disease background induces the expression and exon 10 inclusion of tau in the brain of female mice.

Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models.

Accumulation of β-amyloid (Aβ) and phosphorylated tau in the brain are central events underlying Alzheimers disease (AD) pathogenesis. Aβ is generated from amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase-mediated cleavages. Ubiquilin-1, a ubiquitin-like protein, genetically associates with AD and affects APP trafficking, processing and degradation. Here, we have investigated ubiquilin-1 expression in human brain in relation to AD-related neurofibrillary pathology and the effects of ubiquilin-1 overexpression on BACE1, tau, neuroinflammation, and neuronal viability in vitro in co-cultures of mouse embryonic primary cortical neurons and microglial cells under acute neuroinflammation as well as neuronal cell lines, and in vivo in the brain of APdE9 transgenic mice at the early phase of the development of Aβ pathology. Ubiquilin-1 expression was decreased in human temporal cortex in relation to the early stages of AD-related neurofibrillary pathology (Braak stages 0-II vs. III-IV). There was a trend towards a positive correlation between ubiquilin-1 and BACE1 protein levels. Consistent with this, ubiquilin-1 overexpression in the neuron-microglia co-cultures with or without the induction of neuroinflammation resulted in a significant increase in endogenously expressed BACE1 levels. Sustained ubiquilin-1 overexpression in the brain of APdE9 mice resulted in a moderate, but insignificant increase in endogenous BACE1 levels and activity, coinciding with increased levels of soluble Aβ40 and Aβ42. BACE1 levels were also significantly increased in neuronal cells co-overexpressing ubiquilin-1 and BACE1. Ubiquilin-1 overexpression led to the stabilization of BACE1 protein levels, potentially through a mechanism involving decreased degradation in the lysosomal compartment. Ubiquilin-1 overexpression did not significantly affect the neuroinflammation response, but decreased neuronal viability in the neuron-microglia co-cultures under neuroinflammation. Taken together, these results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation.

Targeting ubiquilin-1 in Alzheimer's disease

Introduction: Alzheimers disease (AD) is a common neurodegenerative disorder affecting an increasing number of people worldwide as the population ages. Currently, there are no drugs available that could prevent AD pathogenesis or slow down its progression. Increasing evidence links ubiquilin-1, an ubiquitin-like protein, into the pathogenic mechanisms of AD and other neurodegenerative diseases. Ubiquilin-1 has been shown to play a key role in the regulation of the levels, subcellular targeting, aggregation and degradation of various neurodegenerative disease-associated proteins. These include the amyloid precursor protein and presenilins that are intimately involved in the mechanisms of AD. Areas covered: Here, the properties and diverse functions of ubiquilin-1 protein in the context of the pathogenesis of AD and other neurodegenerative disorders are discussed. This review recapitulates the available knowledge on the involvement of ubiquilin-1 in the genetic and molecular mechanisms in AD. Furthermore, the association of ubiquilin-1 with specific proteins and mechanisms involved in the pathogenesis of neurodegenerative diseases is described and the known ubiquilin-1-interacting proteins summarized. Expert opinion: The variety of ubiquilin-1-interacting proteins and its central role in the regulation of protein levels and degradation provides a number of novel candidates and approaches for future research and drug discovery.

Regulation of key proteins in Alzheimer’s disease molecular pathogenesis by ubiquilin-1

Background Ubiquilin-1 is a ubiquitin-like protein involved in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders via different mechanisms. UBQLN1 UBQ-8i genetic variation associates with increased AD risk. Ubiquilin-1 protein functions as a molecular chaperone controlling amyloid precursor protein (APP) trafficking and processing and presenilin (PS) levels and subcellular targeting. Ubiquilin-1 harbors a ubiquitin-like (UBL) domain interacting with the proteasome and a ubiquitinassociated (UBA) domain binding polyubiquitinated proteins. Thus, it may target polyubiquitinated proteins to degradation. Alternative splicing of UBQLN1 generates four transcript variants (TV) with varying domain structures, suggesting that diverse variants may specifically interact with and regulate different proteins and cellular functions.

DHCR24 exerts neuroprotection upon inflammation-induced neuronal death

BackgroundDHCR24, involved in the de novo synthesis of cholesterol and protection of neuronal cells against different stress conditions, has been shown to be selectively downregulated in neurons of the affected brain areas in Alzheimer’s disease.MethodsHere, we investigated whether the overexpression of DHCR24 protects neurons against inflammation-induced neuronal death using co-cultures of mouse embryonic primary cortical neurons and BV2 microglial cells upon acute neuroinflammation. Moreover, the effects of DHCR24 overexpression on dendritic spine density and morphology in cultured mature mouse hippocampal neurons and on the outcome measures of ischemia-induced brain damage in vivo in mice were assessed.ResultsOverexpression of DHCR24 reduced the loss of neurons under inflammation elicited by LPS and IFN-γ treatment in co-cultures of mouse neurons and BV2 microglial cells but did not affect the production of neuroinflammatory mediators, total cellular cholesterol levels, or the activity of proteins linked with neuroprotective signaling. Conversely, the levels of post-synaptic cell adhesion protein neuroligin-1 were significantly increased upon the overexpression of DHCR24 in basal growth conditions. Augmentation of DHCR24 also increased the total number of dendritic spines and the proportion of mushroom spines in mature mouse hippocampal neurons. In vivo, overexpression of DHCR24 in striatum reduced the lesion size measured by MRI in a mouse model of transient focal ischemia.ConclusionsThese results suggest that the augmentation of DHCR24 levels provides neuroprotection in acute stress conditions, which lead to neuronal loss in vitro and in vivo.

Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition

cerebellum and thalamus were collected to measure exposure levels of test compounds by liquid chromatography/mass spectroscopy (LC-MS/MS). Results: ZW-104 concentrations in thalamus and cerebellum were dose dependently decreasing in all compound treated groups. The sigmoidal dose response curves for % a4ß2 receptor occupancy was reveals that ABT0594 is a potent compound which requires 0.001 mg/kg of dose to induce 50% receptor occupancy than other compounds. The linear increases in brain and plasma concentration were found for all compounds with respect to dose. Conclusions: The unlabelled ZW-104 was successfully employed for assessing in vivo receptor occupancy for neuronal nicotinic acetylcholine receptor containing a4ß2 in rat by using LC-MS/MS based method. The distribution of ZW-104 in rat brain was consistent with 18F-ZW-104 distribution in baboons. ZW-104 was found faster elimination, less nonspecific binding with high brain penetration than 2FA-85380.

Decreased plasma C-reactive protein levels in APOE ε4 allele carriers

Apolipoprotein E (APOE) ε4 allele is a well‐established risk factor in Alzheimers disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation‐related parameters in population‐based cohorts.

New Implications for the Role for Ubiquilin-1 in Molecular Mechanisms of Alzheime's Disease: Interrelationship with BACE1

Ample evidence links ubiquilins to the pathogenesis of various neurodegenerative disorders. Ubiquilin-1 (also called PLIC-1) is associated to the pathogenesis of Alzheimer’s disease (AD) both genetically and functionally as indicated by investigations in different in vitro and in vivo models and human brain. Previous studies by us and others have identified ubiquilin-1 as a central regulator of the metabolism, subcellular localization, trafficking, as well as accumulation and degradation of various neurodegenerative disease-linked proteins, including the AD-associated β-amyloid precursor protein (APP) and presenilins. Our recent report reveals a previously uncharacterized relationship between ubiquilin-1 and AD-associated β-site cleaving enzyme 1 (BACE1), the rate-limiting enzyme in the generation of the β-amyloid (Aβ) peptides, in cell-based model systems in vitro as well as in the brains of AD model mice in vivo and human patients. Our data suggest that ubiquilin-1 controls BACE1 levels and localization to the late endosomal compartment, the preferred cellular site for Aβ generation. Therefore, the observed decreased levels of ubiquilin-1 in AD brain may result in altered APP processing and Aβ accumulation. Here, we provide a short review on the links between ubiquilin-1 and mechanisms of AD and some other neurodegenerative diseases and then summarize the data in our recent report regarding the newly observed interrelationship between ubiquilin-1 and BACE1.