Diane Jansen

Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease.

Nutritional intervention may retard the development of Alzheimers disease (AD). In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model (APPswe/PS1dE9). One diet contained membrane precursors such as omega-3 fatty acids and uridine monophosphate (DEU), whereas another diet contained cofactors for membrane synthesis as well (Fortasyn); the diets were developed to enhance synaptic membranes synthesis, and contain components that may improve vascular health. We measured cerebral blood flow (CBF) and water diffusivity with ultra-high-field magnetic resonance imaging, as alterations in these parameters correlate with clinical symptoms of the disease. APPswe/PS1dE9 mice on control diet showed decreased CBF and changes in brain water diffusion, in accordance with findings of hypoperfusion, axonal disconnection and neuronal loss in patients with AD. Both multinutrient diets were able to increase cortical CBF in APPswe/PS1dE9 mice and Fortasyn reduced water diffusivity, particularly in the dentate gyrus and in cortical regions. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms.

Gray and white matter degeneration revealed by diffusion in an Alzheimer mouse model.

In patients with Alzheimers disease (AD) the severity of white matter degeneration correlates with the clinical symptoms of the disease. In this study, we performed diffusion-tensor magnetic resonance imaging at ultra-high field in a mouse model for AD (APP(swe)/PS1(dE9)) in combination with a voxel-based approach and tractography to detect changes in water diffusivity in white and gray matter, because these reflect structural alterations in neural tissue. We found substantial changes in water diffusion parallel and perpendicular to axonal tracts in several white matter regions like corpus callosum and fimbria of the hippocampus, that match with previous findings of axonal disconnection and myelin degradation in AD patients. Moreover, we found a significant increase in diffusivity in specific hippocampal subregions, which is supported by neuronal loss as visualized with Klüver-Barrera staining. This work demonstrates the potential of ultra-high field diffusion-tensor magnetic resonance imaging as a noninvasive modality to describe white and gray matter structural changes in mouse models for neurodegenerative disorders, and provides valuable knowledge to assess future AD prevention strategies in translational research.

A Dietary Treatment Improves Cerebral Blood Flow and Brain Connectivity in Aging apoE4 Mice

APOE ε4 (apoE4) polymorphism is the main genetic determinant of sporadic Alzheimers disease (AD). A dietary approach (Fortasyn) including docosahexaenoic acid, eicosapentaenoic acid, uridine, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium has been proposed for dietary management of AD. We hypothesize that the diet could inhibit AD-like pathologies in apoE4 mice, specifically cerebrovascular and connectivity impairment. Moreover, we evaluated the diet effect on cerebral blood flow (CBF), functional connectivity (FC), gray/white matter integrity, and postsynaptic density in aging apoE4 mice. At 10–12 months, apoE4 mice did not display prominent pathological differences compared to wild-type (WT) mice. However, 16–18-month-old apoE4 mice revealed reduced CBF and accelerated synaptic loss. The diet increased cortical CBF and amount of synapses and improved white matter integrity and FC in both aging apoE4 and WT mice. We demonstrated that protective mechanisms on vascular and synapse health are enhanced by Fortasyn, independent of apoE genotype. We further showed the efficacy of a multimodal translational approach, including advanced MR neuroimaging, to study dietary intervention on brain structure and function in aging.

Resting-State Functional Connectivity Changes in Aging apoE4 and apoE-KO Mice

It is well established that the cholesterol-transporter apolipoprotein ε (APOE) genotype is associated with the risk of developing neurodegenerative diseases. Recently, brain functional connectivity (FC) in apoE-ε4 carriers has been investigated by means of resting-state fMRI, showing a marked differentiation in several functional networks at different ages compared with carriers of other apoE isoforms. The causes of such hampered FC are not understood. We hypothesize that vascular function and synaptic repair processes, which are both impaired in carriers of ε4, are the major contributors to the loss of FC during aging. To test this hypothesis, we integrated several different MRI techniques with immunohistochemistry and investigated FC changes in relation with perfusion, diffusion, and synaptic density in apoE4 and apoE-knock-out (KO) mice at 12 (adult) and 18 months of age. Compared with wild-type mice, we detected FC deficits in both adult and old apoE4 and apoE-KO mice. In apoE4 mice, these changes occurred concomitant with increased mean diffusivity in the hippocampus, whereas perfusion deficits appear only later in life, together with reduced postsynaptic density levels. Instead, in apoE-KO mice FC deficits were mirrored by strongly reduced brain perfusion since adulthood. In conclusion, we provide new evidence for a relation between apoE and brain connectivity, possibly mediated by vascular risk factors and by the efficiency of APOE as synaptic modulator in the brain. Our results show that multimodal MR neuroimaging is an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research.

Effects of specific multi-nutrient enriched diets on cerebral metabolism, cognition and neuropathology in AβPPswe-PS1dE9 mice.

Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimers disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AβPPswe-PS1dE9 mice. Starting from 2 months of age, male AβPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1β mRNA levels in AβPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AβPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AβPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders.

Improved spatial learning strategy and memory in aged Alzheimer AβPPswe/PS1dE9 mice on a multi-nutrient diet.

There is accumulating evidence showing that lifestyle factors like diet may influence the onset and progression of Alzheimers disease (AD). Our previous studies suggest that a multi-nutrient diet, Fortasyn, containing nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid, eicosapentaenoic acid, uridine-mono-phosphate, choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium, has an ameliorating effect on cognitive deficits in an AD mouse model. In the present study we analyzed learning strategies and memory of 11-month-old AβPPswe/PS1dE9 (AβPP/PS1) mice in the Morris water maze (MWM) task performed after nine months of dietary intervention with a control diet or a Fortasyn diet to characterize diet-induced changes in cognitive performance. The Fortasyn diet had no significant effect on MWM task acquisition. To assess hippocampus-dependent learning, the strategies that the mice used to find the hidden platform in the MWM were analyzed using the swim path data. During the fourth day of the MWM, AβPP/PS1 mice on control diet more often used the non-spatial random search strategy, while on the Fortasyn diet, the transgenic animals exhibited more chaining strategy than their wild-type littermates. During the probe trial, AβPP/PS1 mice displayed no clear preference for the target quadrant. Notably, in both transgenic and nontransgenic mice on Fortasyn diet, the latency to reach the former platform position was decreased compared to mice on the control diet. In conclusion, this specific nutrient combination showed a tendency to improve searching behavior in AβPP/PS1 mice by increasing the use of a more efficient search strategy and improving their swim efficiency by decreasing the latency to reach the former platform position.

Cholesterol and synaptic compensatory mechanisms in Alzheimer's disease mice brain during aging.

Research into the development of Alzheimers disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid-β deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AβPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old AβPP-PS1 mice compared to age-matched wild-type animals, but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old AβPP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology.

A longitudinal study of cognition, proton MR spectroscopy and synaptic and neuronal pathology in aging wild-type and AβPPswe-PS1dE9 mice.

Proton magnetic resonance spectroscopy (1H MRS) is a valuable tool in Alzheimer’s disease research, investigating the functional integrity of the brain. The present longitudinal study set out to characterize the neurochemical profile of the hippocampus, measured by single voxel 1H MRS at 7 Tesla, in the brains of AβPPSswe-PS1dE9 and wild-type mice at 8 and 12 months of age. Furthermore, we wanted to determine whether alterations in hippocampal metabolite levels coincided with behavioral changes, cognitive decline and neuropathological features, to gain a better understanding of the underlying neurodegenerative processes. Moreover, correlation analyses were performed in the 12-month-old AβPP-PS1 animals with the hippocampal amyloid-β deposition, TBS-T soluble Aβ levels and high-molecular weight Aβ aggregate levels to gain a better understanding of the possible involvement of Aβ in neurochemical and behavioral changes, cognitive decline and neuropathological features in AβPP-PS1 transgenic mice. Our results show that at 8 months of age AβPPswe-PS1dE9 mice display behavioral and cognitive changes compared to age-matched wild-type mice, as determined in the open field and the (reverse) Morris water maze. However, there were no variations in hippocampal metabolite levels at this age. AβPP-PS1 mice at 12 months of age display more severe behavioral and cognitive impairment, which coincided with alterations in hippocampal metabolite levels that suggest reduced neuronal integrity. Furthermore, correlation analyses suggest a possible role of Aβ in inflammatory processes, synaptic dysfunction and impaired neurogenesis.

Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice

Cardiovascular risk factors, especially hypertension, are also major risk factors for Alzheimers disease (AD). To elucidate the underlying vascular origin of neurodegenerative processes in AD, we investigated the relation between systolic blood pressure (SBP) cerebral blood flow (CBF) and vasoreactivity with brain structure and function in a 16-18 months old double transgenic AβPPswe/PS1dE9 (AβPP/PS1) mouse model for AD. These aging AβPP/PS1 mice showed an increased SBP linked to a declined regional CBF. Furthermore, using advanced MRI techniques, decline of functional and structural connectivity was revealed in the AD-like mice coupled to impaired cognition, increased locomotor activity, and anxiety-related behavior. Post mortem analyses demonstrated also increased neuroinflammation, and both decreased synaptogenesis and neurogenesis in the AβPP/PS1 mice. Additionally, deviant levels of fatty acids and sterols were present in the brain tissue of the AβPP/PS1 mice indicating maladapted brain fatty acid metabolism. Our findings suggest a link between increased SBP, decreased cerebral hemodynamics and connectivity in an AD mouse model during aging, leading to behavioral and cognitive impairments. As these results mirror the complex clinical symptomatology in the prodromal phase of AD, we suggest that this AD-like murine model could be used to investigate prevention and treatment strategies for early AD patients. Moreover, this study helps to develop more efficient therapies and diagnostics for this very early stage of AD.