Actions and interactions of the IGF system in Alzheimer’s disease: review and hypotheses

Insulin-like growth factors (IGF) are pleiotrophic polypeptides affecting all aspects of growth and development. The IGF system, including ligands, receptors, binding proteins and proteases is also involved in pathophysiological conditions, such as cancer and degenerative conditions. In this review, the actions and interactions of the IGF system as it relates to Alzheimer’s disease will be investigated.     

Brain cellular senescence in mouse models of Alzheimer’s disease

The accumulation of senescent cells contributes to aging pathologies, including neurodegenerative diseases, and its selective removal improves physiological and cognitive function in wild-type mice as well as in Alzheimer’s disease (AD) models. AD models recapitulate some, but not all components of disease and do so at different rates. Whether brain cellular senescence is recapitulated in some or all AD models and whether the emergence of cellular senescence in AD mouse models occurs before or after the expected onset of AD-like cognitive deficits in these models are not yet known. The goal of this study was to identify mouse models of AD and AD-related dementias that develop measurable markers of cellular senescence in brain and thus may be useful to study the role of cellular senescence in these conditions. We measured the levels of cellular senescence markers in the brains of P301S(PS19), P301L, hTau, and 3xTg-AD mice that model amyloidopathy and/or tauopathy in AD and related dementias and in wild-type, age-matched control mice for each strain. Expression of cellular senescence markers in brains of transgenic P301L and 3xTg-AD mice was largely indistinguishable from that in WT control age-matched mice. In contrast, markers of cellular senescence were differentially increased in brains of transgenic hTau and P301S(PS19) mice as compared to WT control mice before the onset of AD-like cognitive deficits. Taken together, our data suggest that P301S(PS19) and hTau mice may be useful models for the study of brain cellular senescence in tauopathies including, but not limited to, AD.

     

In vivo characterization of endothelial cell activation in a transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD is characterized by an excessive cerebral amyloid deposition leading to degeneration of neurons and eventually to dementia. It has been shown by epidemiological studies that cardiovascular drugs with an anti-angiogenic effect can influence the outcome of AD patients. Therefore, it has been speculated that in AD angiogenesis in the brain vasculature may play an important role. Here we report that in the brain of APP23 mice – a transgenic model of AD – after deposition of amyloid in blood vessels endothelial cell activation occurs in an age-dependent manner. Amyloid deposition is followed by the expression of β3-integrin, a specific marker molecule of activated endothelium. The β3-integrin expression is restricted to amyloid-positive vessels. Moreover, homogenates of the brains of APP23 mice induced the formation of new vessels in an in vivo angiogenesis assay. Vessel formation could be blocked by the VEGF antagonist SU 4312 as well as by statins, suggesting that these drugs may interfere with endothelial cell activation in AD. In conclusion our results indicate that amyloid deposition in the vasculature leads to endothelial cell apoptosis and endothelial cell activation, which can be modulated by anti-angiogenic drugs.     

Biochemical alterations of the striatum in an MPTP-treated mouse model of Parkinson’s disease

We investigated the biochemical alterations of the striatum of mice subjected to seven experimental schedules with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment. The mice were treated intraperitoneally (i.p.) with MPTP (20 mg/kg in saline) four times a day at 2-hr intervals showed severe and persistent depletions of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, as compared with those (1) treated with MPTP (15 mg/kg in saline, i.p.) once a day for 14 consecutive days; (2)MPTP (30 mg/kg in saline, i.p.) twice a day for 5 consecutive days; (3) MPTP (10 mg/kg in saline, i.p.) four times a day at 1-hr intervals for 2 consecutive days; (4) MPTP (20 mg/kg in saline, i.p.) once a day for 4 consecutive days; (5) MPTP (20 mg/kg in saline, i.p.) twice a day for 2 consecutive days; (6) MPTP (20 mg/kg in saline, i.p.) twice a day for 4 consecutive days. In our Western blot analysis, furthermore, the mice that received MPTP (20 mg/kg in saline) four times a day at 2-hr intervals showed a severe decrease of the striatal tyrosine hydroxylase (TH) protein levels and a significant increase of the striatal glial fibrillary acidic protein (GFAP) levels. These results demonstrate that the model with acute MPTP treatment can cause severe neuronal damage in the mouse striatum, as compared to the model with continuous treatment with MPTP. Thus our findings may support the validity of acute MPTP treatment model for unraveling in the neurodegenerative processes in PD.     

Beneficial effects of levetiracetam in streptozotocin-induced rat model of Alzheimer’s disease

Metabolic Brain Disease - Alzheimer’s disease (AD) is the most common neurodegenerative disorder among the elderly. In the light of increasing AD prevalence and lack of effective treatment,...     

Role of metals in Alzheimer’s disease

Metabolic Brain Disease - Metal homeostasis in the central nervous system (CNS) is a crucial component of healthy brain function, because metals serve as enzymatic cofactors and are key components...     

Co-localization of hyperphosphorylated tau and caspases in the brainstem of Alzheimer’s disease patients

Hyperphosphorylation of microtubule associated protein tau had limited studies in Alzheimer’s disease (AD) brainstem. We compared the distribution and number of neurons with hyperphosphorylated tau in two age groups of AD brainstems with mean ages of 65.4 ± 5.7 and 91.1 ± 6.4 years. The degree of co-localization of hyperphosphorylated tau positive cells with either cleaved caspase-3 or cleaved caspase-6 was also quantified. Results showed hyperphosphorylated tau mainly occurred in hypoglossal, dorsal motor vagal, trigeminal sensory/motor nuclei as well as in dorsal raphe, locus coeruleus and substantia nigra. Older AD brainstem consistently had higher density of hyperphosphorylated tau cells. Up to 70% of tau positive cells also displayed either cleaved caspase-3 or caspase-6, and the number of co-localized tau cells in each caspase subfamily group was always higher in older aged group. Some hyperphosphorylated tau cells with cleaved caspases had TUNEL positive nuclei. These findings suggest that these latter cells went through the apoptotic process or DNA fragmentation.     

Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer’s disease

GeroScience - In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with...     

Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson’s disease

We examined the effects of 7-nitroindazole on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h-intervals. Administration of 7-nitroindazole showed dose-dependent neuroprotective effects against striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 7 days after MPTP treatment. Behavioral testing showed that MPTP-treated mice exhibited motor deficits in the catalepsy test after 7 days, but 7-nitroindazole prevented the appearance of motor abnormalities in this test. The MPTP-treated mice exhibited the loss of tyrosine hydroxylase-containing dopaminergic neurons in mice after 1, 3 and 7 days, but 7-nitroindazole-treated mice showed a protective effect. GFAP (glial fibrillary acidic protein)-positive astrocytes were accumulated in the striatum 3 and 7 days and in the substantia nigra 1, 3 and 7 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant increase in the number of GFAP-positive astrocytes in the striatum and substantia nigra after MPTP treatment. The reactive astrocytes in the striatum and substantia nigra after MPTP treatment increased the production of S100β protein, which is thought to promote neuronal damage, but 7-nitoindazole suppressed the expression of S100 β protein. Activation of microglia, with an increase in staining intensity and morphological changes, was observed in the striatum and substantia nigra 1 and 3 days after MPTP treatment, but 7-nitroindazole prevented a significant increase in the number of isolectin B₄ positive microglia in the striatum and substantia nigra. On the other hand, nestin- immunoreactive cells were increased significantly in the striatum 3 and 7 days after MPTP treatment. 7-Nitroindazole treatment facilitated nestin expression in the striatum 7 days after MPTP treatment. Thus, nNOS inhibitor 7-nitroindazole protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated though the modulation of glial activation, including the inhibition of S100β synthesis and the prevention of microglial activation. These results suggest the therapeutic strategy targeted to glial modulation with 7-nitoindazole offers a great potential for the development of new neuroprotective therapies for Parkinson’s disease.     

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Axon pathology has been widely reported in Alzheimer’s disease (AD) patients and AD mouse models. Herein we report that increased miR-342–5p down-regulates the expression of ankyrin G (AnkG), a protein known to play a critical role in establishing selective filtering machinery at the axon initial segment (AIS). Diminished AnkG expression leads to defective AIS filtering in cultured hippocampal neurons from AD mouse models, as monitored by selective exclusion of large macromolecules from the axons. Furthermore, AnkG-deficiency impairs AIS localization of Na_v 1.6 channels and confines NR2B to the somatodendritic compartments. The expression of exogenous AnkG improved the cognitive performance of 12-mo-old APP/PS1 mice; thus, our data suggest that AnkG and impairment of AIS filtering may play important roles in AD pathology.Alzheimer’s disease (AD), the most common cause of dementia in individuals age >65 y, is associated with impairments in memory, language, behavior, and cognition (1). The brain of AD patients is characterized by extracellular senile plaques composed of amyloid β (Aβ), intracellular tau aggregates known as neurofibrillary tangles, and neuronal loss (1). Axonal pathology, including axonal swellings and abnormal accumulation of axonal proteins, is associated with dystrophic neurites and amyloid plaque formation in AD (2). Abundant age-dependent axonal spheroids and myelin ovoids have been reported in the spinal cord of APP_Swe/London/PS1_M146V mice, an established familial form of AD (FAD) transgenic mouse model (3); however, the cause of the axonopathy and the pathways involved in axonal abnormalities in AD remain largely unknown.MicroRNAs (miRNAs) are a class of conserved, short, noncoding RNAs (4–8), many of which have demonstrated implications in AD (9–11). We have previously reported that miR-342–5p is up-regulated in APP/PS1, PS1ΔE9, and PS1-M146V transgenic AD mice, which is mechanistically linked to elevated β-catenin, c-Myc, and IFN regulatory factor (IRF)-9 (12). MiRNAs interact with the 3′ UTR or 5′ UTR region of complementary mRNA sequences (13), inducing translation repression or target degradation (14, 15). In previous work, we demonstrated that increased miR-342–5p down-regulates the expression of ankyrin G (AnkG) (12), a protein known to play a critical role at the axon initial segment (AIS).The AIS is known to play an important role in neuronal polarity formation, action potential initiation (16, 17), and brain diseases and injury (18). At the AIS, a plasma membrane barrier segregates the axonal from the somatodendritic membrane compartments (19), and a filtering machinery sorts cytoplasmic components that are destined for transport into the axon (19, 20). In cultured embryonic rat hippocampal neurons at embryonic day (E) 18, a selective filter develops at 5 d in vitro (DIV; 2 d after axon/dendrite differentiation), with an average pore size of ≤13 nm (20). This physical barrier may represent a high-density meshwork at the AIS composed of actin and AnkG. AnkG has been demonstrated to play an important role in maintaining the structure of AIS and in the generation/maintenance of neuronal polarity (21–24). This filtering machinery is critical for selective transport of macromolecules into the axon; for example, KIF5-driven carriers of the synaptic vesicle protein VAMP2, but not KIF17-driven carriers of dendrite-targeting NMDA receptor subunit NR2B, can enter the axon (20). Thus, selective filtering at the AIS is suggested to contribute to preferential trafficking and segregation of cellular components in polarized neurons (20).Herein we report that in APP/PS1, PS1ΔE9, and PS1-M146V mouse hippocampal neurons, down-regulation of AnkG by miR-342–5p results in impairment of selective filtering at the AIS in these AD transgenic mouse neurons, and that ectopic expression of AnkG reverses AIS filtering abnormalities. The deficits of the filtering machinery in the AIS of APP/PS1 mice lead to mislocation of the Na_v 1.6 channels and the NR2B. Taken together, our results point to an aberrant AnkG-defective AIS filtering mechanism as a critical determinant of axonal and neuronal pathology in AD mouse models.     

Promising protein biomarkers in the early diagnosis of Alzheimer’s disease

Metabolic Brain Disease - Alzheimer’s disease (AD) is an insidious, multifactorial disease that involves the devastation of neurons leading to cognitive impairments. Alzheimer’s have...     

Association between the characteristics of metabolic syndrome and Alzheimer’s disease

Various epidemiological studies have shown that type 2 diabetes and metabolic syndrome are highly correlated with Alzheimer’s disease (AD). Here, we sought to assess the impact of metabolic syndrome characteristics on the progression of AD. Five-week-old male, spontaneously hypertensive (n?=?32) and Wistar Kyoto (abbreviated WKY; n?=?8) rats were divided into 5 groups (each n?=?8): WKY, hypertension (HTN), streptozotocin-induced diabetes (STZ), high-fat diet (HFD), and STZ + high-fat diet-induced diabetes mellitus (DM). All animals were sacrificed and samples of the blood, liver, and brain were collected for further biological analysis. During the 15-week period of induction, the STZ and DM groups (animals injected with low-dose STZ) had significantly higher fasting glucose levels; the HFD group had elevated insulin levels, but normal blood glucose levels. The HFD and DM groups had hypercholesterolemia and higher hepatic levels of triglycerides and cholesterol. Additionally, correlations between HFD and elevated brain amyloid-beta 42 (Aβ-42), hyperglycemia and down-regulation of brain insulin receptor, and serum Aβ-42 and hepatic triglyceride concentrations (r²?=?0.41, p?<?0.05) were observed. Serum C-reactive protein and malondialdehyde did not appear to have a significant influence on the association with biomarkers of AD. Thus, our study demonstrated that rats with characteristics of metabolic syndrome had a large number of biomarkers predicting AD; however, no relationship between traditional inflammatory and oxidative markers and AD was found. Further studies are necessary to prove that these findings in rats are relevant to AD processes in humans.     

Neurodegeneration of the retina in mouse models of Alzheimer’s disease: what can we learn from the retina?

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease commonly found among elderly. In addition to cognitive and behavioral deficits, vision abnormalities are prevalent in AD patients. Recent studies investigating retinal changes in AD double-transgenic mice have shown altered processing of amyloid precursor protein and accumulation of β-amyloid peptides in neurons of retinal ganglion cell layer (RGCL) and inner nuclear layer (INL). Apoptotic cells were also detected in the RGCL. Thus, the pathophysiological changes of retinas in AD patients are possibly resembled by AD transgenic models. The retina is a simple model of the brain in the sense that some pathological changes and therapeutic strategies from the retina may be observed or applicable to the brain. Furthermore, it is also possible to advance our understanding of pathological mechanisms in other retinal degenerative diseases. Therefore, studying AD-related retinal degeneration is a promising way for the investigation on (1) AD pathologies and therapies that would eventually benefit the brain and (2) cellular mechanisms in other retinal degenerations such as glaucoma and age-related macular degeneration. This review will highlight the efforts on retinal degenerative research using AD transgenic mouse models.     

Metabolic disorder in Alzheimer’s disease

Metabolic Brain Disease - Alzheimer’s disease (AD), a well known aging-induced neurodegenerative disease is related to amyloid proteinopathy. This proteinopathy occurs due to abnormalities in...     

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

Alzheimer’s disease is the leading cause of dementia and the most prevalent neurodegenerative disease. It is an aging-related multi-factorial disorder and growing evidence support the contribution of metabolic factors to what was formerly thought to be a centrally mediated process. Obesity has already been recognized as an important player in the pathogenesis of this type of dementia, independently of insulin resistance or other vascular risk factors. Although the exact underlying mechanisms are still unknown, adipocyte dysfunction and concomitant alteration in adipocyte-derived protein secretion seem to be involved, since these adipocytokines can cross the blood–brain barrier and influence cognitive-related structures. Very few studies have assessed the role of adipocytokines dysfunction on cognitive impaired patients and yielded contradictory results. Interestingly, extensive research on the central effects of leptin in Alzheimer’s disease-transgenic mice has demonstrated its capacity to enhance synaptic plasticity and strength, as well as to prevent beta-amyloid deposition and tau phosphorylation. In addition, adiponectin, the most abundant adipocytokine whose levels are inversely correlated to adiposity, has shown to be neuroprotective to hippocampal cells. Many other adipose-derived cytokines have mainly pro-inflammatory properties, being able to trigger and/or enhance central inflammatory cascades and also to influence the secretion of other adipocytokines involved in cognition. This paper pretends to review the existing evidence on the contribution of adipocytokines dysfunction to the increased risk of dementia associated with mid-life obesity, unraveling its insulin-independent effects on cognition.     

Distinctive features of microsaccades in Alzheimer’s disease and in mild cognitive impairment

During visual fixation, the eyes are never completely still, but produce small involuntary movements, called “fixational eye movements,” including microsaccades, drift, and tremor. In certain neurological disorders, attempted fixation results in abnormal fixational eye movements with distinctive characteristics. Thus, determining how normal fixation differs from pathological fixation has the potential to aid early and differential noninvasive diagnosis of neurological disease as well as the quantification of its progression and response to treatment. Here, we recorded the eye movements produced by patients with Alzheimer’s disease, patients with mild cognitive impairment, and healthy age-matched individuals during attempted fixation. We found that microsaccade magnitudes, velocities, durations, and intersaccadic intervals were comparable in the three subject groups, but microsaccade direction differed in patients versus healthy subjects. Our results indicate that microsaccades are more prevalently oblique in patients with Alzheimer’s disease or mild cognitive impairment than in healthy subjects. These findings extended to those microsaccades paired in square-wave jerks, supporting the hypothesis that microsaccades and square-wave jerks form a continuum, both in healthy subjects and in neurological patients.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-013-9582-3) contains supplementary material, which is available to authorized users.