BackgroundThe study of late-onset/age-related Alzheimer’s disease (AD)(sporadic AD, 95% of AD cases) has been hampered by a paucity of animal models. Oxidative stress is considered a causative factor in late onset/age-related AD, and aldehyde dehydrogenase 2 (ALDH2) is important for the catabolism of toxic aldehydes associated with oxidative stress. One such toxic aldehyde, the lipid peroxidation product 4-hydroxynonenal (HNE), accumulates in AD brain and is associated with AD pathology. Given this linkage, we hypothesized that in mice lacking ALDH2, there would be increases in HNE and the appearance of AD-like pathological changes.ResultsChanges in relevant AD markers in Aldh2-/- mice and their wildtype littermates were assessed over a 1 year period. Marked increases in HNE adducts arise in hippocampi from Aldh2-/- mice, as well as age-related increases in amyloid-beta, p-tau, and activated caspases. Also observed were age-related decreases in pGSK3β, PSD95, synaptophysin, CREB and pCREB. Age-related memory deficits in the novel object recognition and Y maze tasks begin at 3.5-4 months and are maximal at 6.5-7 months. There was decreased performance in the Morris Water Maze task in 6 month old Aldh2-/- mice. These mice exhibited endothelial dysfunction, increased amyloid-beta in cerebral microvessels, decreases in carbachol-induced pCREB and pERK formation in hippocampal slices, and brain atrophy. These AD-associated pathological changes are rarely observed as a constellation in current AD animal models.ConclusionsWe believe that this new model of age-related cognitive impairment will provide new insight into the pathogenesis and molecular/cellular mechanisms driving neurodegenerative diseases of aging such as AD, and will prove useful for assessing the efficacy of therapeutic agents for improving memory and for slowing, preventing, or reversing AD progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0117-y) contains supplementary material, which is available to authorized users.

Oxidative damage resulting from increased lipid peroxidation (LPO) is considered an important factor in the development of late onset/age-related Alzheimer’s disease (AD). Deuterium-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to the reactive oxygen species-initiated chain reaction of LPO than regular hydrogenated (H-) PUFAs. We investigated the effect of D-PUFA treatment on LPO and cognitive performance in aldehyde dehydrogenase 2 (Aldh2) null mice, an established model of oxidative stress-related cognitive impairment that exhibits AD-like pathologies. Mice were fed a Western-type diet containing either D- or H-PUFAs for 18 weeks. D-PUFA treatment markedly decreased cortex and hippocampus F2-isoprostanes by approximately 55% and prostaglandin F2α by 20–25% as compared to H-PUFA treatment. D-PUFAs consistently improved performance in cognitive/memory tests, essentially resetting performance of the D-PUFA-fed Aldh2−/− mice to that of wildtype mice fed a typical laboratory diet. D-PUFAs therefore represent a promising new strategy to broadly reduce rates of LPO, and combat cognitive decline in AD.

No abstract

BackgroundClinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer’s disease (AD) therapeutic strategies. The mixed pathology reported in a large population of AD patients demands a multifunctional drug approach. Since activation of cAMP response element binding protein (CREB) plays a crucial role in synaptic strengthening and memory formation, we retooled a clinical drug with known neuroprotective and anti-inflammatory activity to activate CREB, and validated this novel multifunctional drug, NMZ, in 4 different mouse models of AD.ResultsNMZ was tested in three mouse models of familial AD and one model of sporadic AD. In 3 × Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with robust cognitive deficits. NMZ treatment lowered neurotoxic forms of Aβ in both APP/PS1 and 3 × Tg transgenic mice while also restoring neuronal plasticity biomarkers in the 3 × Tg mice. In EFAD mice, incorporation of the major genetic AD risk factor, hAPOE4, did not mute the beneficial drug effects. In a novel sporadic mouse model that manifests AD-like pathology caused by accelerated oxidative stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function.ConclusionsThe multifunctional approach, embodied by NMZ, was successful in mouse models of AD incorporating Aβ pathology (APP/PS1), tau pathology (3xTg), and APOE4, the major human genetic risk factor for AD (EFAD). The efficacy observed in a novel model of sporadic AD (Aldh2−/−) demonstrates that the therapeutic approach is not limited to rare, familial AD genetic mutations. The multifunctional drug, NMZ, was not designed directly to target Aβ and tau pathology; however, the attenuation of this hallmark pathology suggests the approach to be a highly promising, disease-modifying strategy for AD and mixed pathology dementia.

No abstract

No abstract

Most current mouse models Alzheimer’s disease (AD) exhibit pathological changes dependent on overexpression of mutant human genes linked to familial AD, and animal models that mirror late‐onset/age‐related AD (95% of AD cases) are lacking. Oxidative stress is considered a causative factor in age‐related AD, and Aldehyde dehydrogenase 2 (ALDH2) is important for the detoxification of endogenous aldehydes, such as 4‐hydroxynonenal (HNE), a lipid peroxidation product formed during periods of oxidative stress that can form protein adducts, altering cell function. HNE adducts accumulate in the brains of AD patients and are associated with AD pathology. Given this linkage, manipulations that increase HNE levels might be expected to result in biochemical and cognitive changes that mirror those found in AD. Accordingly, we followed the age‐related changes of a number of relevant AD markers over a 12 month period in hippocampal homogenates from Aldh2 null mice. Marked increases in HNE adduct formation occurred as early as 3 months, and there were age‐related increases in monomeric amyloid β (Aβ), phospho tau protein, and activated caspases 3 and 6. Also observed were age‐related decreases in PSD95 and synaptophysin (indicating synaptic loss) and of total and phosphorylated cAMP‐response element binding protein (CREB). Aldh2 null mice exhibit a graded, age‐related decrease in performance in recognition and spatial memory tasks beginning at 3 months of age and maximal at 6 months. These mice also exhibit dystrophic neurites and loss of dendritic spines, defects in cholinergic agonist‐induced CREB phosphorylation, endothelial dysfunction, and monomeric and oligomeric Aβ deposition in cerebral microvessels. Aldh2 null mice exhibit a wide spectrum of AD‐like pathological changes that are rarely observed together in current AD animal models, and may prove useful for assessing the efficacy of therapeutic agents for improving memory and for slowing, preventing, or reversing disease progression. Grant Funding Source: Botterell Foundation

No abstract