Effect of cortistatin on tau phosphorylation at Ser262 site

The development of intraneuronal lesions as a result of the progressive deposition of hyperphosphorylated tau at specific brain regions (such as hippocampus and cortex) plays a key role in the pathological process of Alzheimer's disease. However, the mechanisms by which tau phosphorylation is regulated, mainly in the pathology found in the cortex, are still poorly understood. Here, we analyzed the effect of cortistatin, a cortical neuropeptide related to somatostatin, on tau phosphorylation at Ser262 in cultures of murine cortical neurons. Both somatostatin and cortistatin induce tau phosphorylation at Ser262, a site modified in Alzheimer's disease, although with different kinetics in cortex. The effect of cortistatin likely is mediated by heterodimeric receptors composed of somatostatin receptor subtypes 2 and 4 and also by protein kinase C signaling. Cortistatin-deficient mice show decreased tau phosphorylation at Ser262 in the cortex but not in other brain regions tested. Our results suggest an important role for cortistatin in the regulation of tau phosphorylation that may be associated with the pathophysiology of Alzheimer's disease in regions such as the cerebral cortex.     

Does parkin play a role in the peripheral nervous system? A family report

Two genes were identified for autosomal recessive forms of early onset Parkinson's disease: parkin and DJ-1. We describe 2 siblings with EOPD due to parkin mutations and peripheral neuropathy, which presented as neuropathy with liability to pressure palsies (HNPP) in the index case. RT-PCR experiments revealed that the parkin gene is expressed in sural nerves from both controls and patient with parkin-related disease. Our findings support the view that parkin may play a role in the peripheral nervous system.     

Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease

Huntington's disease (HD) is a heritable neurodegenerative disorder, characterised by metabolic disturbances, along with cognitive and psychiatric impairments. Targeting metabolic HD dysfunction via the maintenance of body weight and fat mass and restoration of peripheral energy metabolism can improve the progression of neurological symptoms. In this respect, we focused on the therapeutic potential of the orexigenic peptide hormone ghrelin, which plays an important role in promoting a positive energy balance. In the present study, we found a significant disruption of circadian metabolic regulation in a R6/2 mouse HD model in the late stage of disease. Daily circadian rhythms of activity, energy expenditure, respiratory exchange ratio and feeding were strongly attenuated in R6/2 mice. During the rest phase, R6/2 mice had a higher total activity, elevated energy expenditure and excessive water consumption compared to control mice. We also found that, in the late stage of disease, R6/2 mice had ghrelin axis deficiency as a result of low circulating ghrelin levels, in addition to down‐regulation of the ghrelin receptor and several key signalling molecules in the hypothalamus, as well as a reduced responsiveness to exogenous peripheral ghrelin. We demonstrated that, in pre‐symptomatic mice, responsiveness to ghrelin is preserved. Chronic ghrelin treatment efficiently increased lean body mass and decreased the energy expenditure and fat utilisation of R6/2 mice in the early stage of disease. In addition, ghrelin treatment was also effective in the normalisation of drinking behaviour and the rest activity of these mice. Ghrelin treatment could provide a novel therapeutic possibility for delaying disease progression; however, deficiency in ghrelin receptor expression could limit its therapeutic potential in the late stage of disease.     

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

Lewy body (LB) diseases are characterized by alpha‐synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non‐LB diseases including atypical parkinsonism and non‐LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD. © 2014 International Parkinson and Movement Disorder Society     

β-Amyloid peptide induced cytoskeletal reorganization in cultured astrocytes

The effects of β-amyloid (25–35) (βA) on cultured astrocytes from rat cortex were studied and compared with those of a scrambled peptide and with untreated cultures. Single addition (from 5 to 200 μg/ml) of βA peptide induced a marked morphological change in astrocytes, changing their flat polygonal shape into stellate process-bearing morphology. The changes induced by βA were concentration and time-dependent. The addition of the scrambled peptide did not alter cell viability in comparison with untreated astrocyte cultures. However, cell viability was dose-dependently decreased by βA. A subpopulation of βA-treated astrocytes showed an increase in glial fibrillary acidic protein (GFAP) and Vimentin (Vim) immunostaining while other reactive astrocyte markers such as S100β, MAP2, and ApoE remained unaltered or undetectable. The morphological changes in βA-treated astrocytes appeared to be mainly due to a cytoskeletal reorganization, since the total amounts of GFAP and Vim proteins were not essentially modified. These results strongly suggest that astrocytes are another cellular target of the effects of βA and this may be relevant to understanding the neuropathology of Alzheimer's disease. J. Neurosci. Res. 47:216–223, 1997. © 1997 Wiley-Liss, Inc.     

Interleukin-2 receptor in peripheral blood lymphocytes of Alzheimer's disease patients.

In this study, we investigated the differences in the incidence rate of human leukocyte antigen-DR (HLA-DR) and interleukin 2 receptor (IL-2R) in the peripheral blood lymphocytes of 13 women who were diagnosed clinically as having Alzheimer's disease (AD group), and 13 healthy women with no mental disorders (control group). As a result, the AD group showed a markedly higher rate of lymphocyte subsets of CD4+HLA-DR+, CD4+IL-2R+, CD8+HLA-DR+, CD8-HLA-DR+ and CD8+IL-2R+. This finding indicates a possible immune reaction occurring in the peripheral blood of AD patients. In addition, these higher rates correlate well with the changes in the immune system reported in the postmortem brains of AD patients. Our findings indicate that immunological interactions exist between the central nervous system and the peripheral blood lymphocytes of AD patients, and AD might be induced by an immune reaction occurring in the brain.     

Rimantadine in Parkinson's disease patients experiencing peripheral adverse effects from amantadine: report of a case series.

We report our experience with 7 consecutive patients with Parkinson's disease (PD) who received rimantadine (the alpha-methyl derivative of amantadine) in substitution of amantadine due to peripheral side effects (lower limb edema, livedo reticularis). Mean age was 67.3 +/- 5.9 years, the mean disease duration was 13 +/- 6.3 years, and mean Hoehn and Yahr stage was 2.2 +/- 0.4. A total of 3 patients experienced marked improvement of edema, and 1 patient experienced marked improvement of livedo reticularis. Only 1 of the 7 patients reported significant loss of motor benefit when amantadine was replaced with rimantadine. Our results demonstrate that rimantadine may be considered as an alternative to amantadine in patients experiencing amantadine-induced peripheral side effects.     

Glycation in Parkinson's disease and Alzheimer's disease

Glycation is a spontaneous age‐dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α‐synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society     

Mechanisms underlying synaptic vulnerability and degeneration in neurodegenerative disease

Recent developments in our understanding of events underlying neurodegeneration across the central and peripheral nervous systems have highlighted the critical role that synapses play in the initiation and progression of neuronal loss. With the development of increasingly accurate and versatile animal models of neurodegenerative disease it has become apparent that disruption of synaptic form and function occurs comparatively early, preceding the onset of degenerative changes in the neuronal cell body. Yet, despite our increasing awareness of the importance of synapses in neurodegeneration, the mechanisms governing the particular susceptibility of distal neuronal processes are only now becoming clear. In this review we bring together recent developments in our understanding of cellular and molecular mechanisms regulating synaptic vulnerability. We have placed a particular focus on three major areas of research that have gained significant interest over the last few years: (i) the contribution of synaptic mitochondria to neurodegeneration; (ii) the contribution of pathways that modulate synaptic function; and (iii) regulation of synaptic degeneration by local posttranslational modifications such as ubiquitination. We suggest that targeting these organelles and pathways may be a productive way to develop synaptoprotective strategies applicable to a range of neurodegenerative conditions.     

Evidence for small fiber neuropathy in early Parkinson's disease

IntroductionParkinson's disease (PD) is neurodegenerative movement disorder affecting primarily the central nervous system with several recognized non-motor symptoms that can occur at various stages of the disease. Recently it has been shown that patients with PD may be prone to peripheral nervous system pathology in the form of a peripheral neuropathy (PN). It is unclear if PN is an inherent feature of PD or if it is an iatrogenic effect of the mainstay PD treatment Levodopa.MethodsTo determine if peripheral neuropathy occurs in early untreated PD we employed a case-control study design using gold standard tests for PN, including neurological examination according to the Utah Early Neuropathy Scale (UENS) and nerve conduction studies, as well as new, more sensitive and informative tests for PN including the skin biopsy and corneal confocal microscopy (CCM).ResultsWe studied 26 patients with PD and 22 controls using the neurological examination and nerve conduction studies (NCS) and found no significant difference between groups except for some reduced vibration sense in the PD group. Epidermal nerve densities in the skin biopsies were similar between our cohorts. However, using CCM – a more sensitive test and a surrogate marker of small fiber damage in PN, we found that patients with PD had significantly reduced corneal nerve fiber densities and lengths as compared to controls.ConclusionsWe conclude that our positive CCM results provide evidence of preclinical PN in newly diagnosed PD patients.     

Clinical measures of progression in Parkinson's disease

Despite all recent advances in symptomatic therapy Parkinson's disease (PD) continues to be a relentlessly progressive neurodegenerative disorder. Therefore therapies that will slow or hold disease progression are a major medical unmet need in PD. Clinical measures of disease progression that have been used in disease modification trials so far have focused on indices of progression of cardinal motor features like bradykinesia, rigidity, and tremor as captured by the UPDRS and the emerging need for effective dopaminergic symptomatic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites in the brain or peripheral autonomic nervous system contribute to poorly levodopa responsive motor symptoms like postural instability, freezing and falls or nonmotor symptoms. In addition treatment‐induced motor complications also impact on PD disability. Although it is widely accepted that clinical progression of PD is multidimensional and in addition includes effects of aging, there is no consensus how to best implement more clinically meaningful endpoints for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers for disease progression that would faithfully reflect advancing neurodegeneration and resulted clinical disability in PD and that could be used in shorter term clinical trials testing putative disease modifying agents. © 2009 Movement Disorder Society     

Ultrastructural localization of somatostatin-like immunoreactivity in the rat dentate gyrus

Neurons containing somatostatin (SOM) are enriched in the dentate gyrus. We sought to establish the ultrastructural localization of this peptide in the dentate gyrus of the rat brain with a double-bridged peroxidase-antiperoxidase (PAP) method localizing antisera directed against somatostatin (SOM)-28 and SOM-28. Initial light microscopic observations confirmed that the majority of perikarya and thick varicose processes with intense SOM-like immunoreactivity (SOM-LI) were observed in the hilus. Fine varicose processes with SOM-LI were found throughout all layers of the dentate gyrus but were most intense in the outer third of the molecular layer (ML), where an occasional perikaryon with SOM-LI was seen. By electron microscopy, SOM-LI was found in neuronal perikarya, dendrites, axons, and axon terminals. Two types of SOM-containing perikarya were observed. The first type was small (6-10 microns), round or avoid, and had a labeled cytoplasma with abundant Golgi complexes and a dense accumulation of PAP-reaction product. The second type of perikarya was larger (11-16 microns) and had a more abundant cytoplasm than the first type, but the Golgi complexes did not appear labeled. Most (96% of 374) of the synapses on the SOM-labeled perikarya and dendrites were from terminals without SOM-LI which formed nearly equal proportions of asymmetric and symmetric junctions. The remainder of the presynaptic terminals contained SOM-LI and made primarily symmetric synapses. Synaptic junctions from both unlabeled and labeled terminals were primarily on the shafts of the small (0.5-1.5 microns) SOM-immunoreactive dendrites. The terminals with SOM-LI (0.25-1.3 microns) contained many small, clear vesicles and from zero to four large dense-core vesicles. Terminals with SOM-LI were associated 1) with one unlabeled perikaryon or dendrite (49% of 215 in the hilus; 76% of 326 in the ML); 2) with two unlabeled perikarya or dendrites simultaneously (5% hilus; 4% ML); and 3) with one SOM-containing perikaryon or dendrite (6% hilus; 3% ML). In all three types of associations, synaptic contacts on perikarya were few while the majority were with small (distal) dendrites. Moreover, most of the terminals with SOM-LI formed symmetric junctions or lacked membrane specializations but were without any apparent glial intervention in the plane of section analyzed. The remaining SOM-labeled terminals (40% hilus; 17% ML) were without any apparent synaptic relations. However, a few of these terminals were in direct apposition to other terminals, some of which were also SOM-immunoreactive.(ABSTRACT TRUNCATED AT 400 WORDS)     

Somatostatin genetic variants modify the risk for Alzheimer's disease among Finnish patients

The levels of somatostatin are consistently decreased in the brain and cerebrospinal fluid of Alzheimer's disease (AD) patients. The somatostatin gene is located on chromosome 3q27.3 close to an association region identified in late-onset AD patients originating from Finland. Since somatostatin is a good candidate on both positional and functional grounds, we studied whether single nucleotide polymorphisms (SNPs) in the somatostatin gene were associated with AD in the Finnish population. We genotyped three SNPs within this gene in Finnish AD patients (n = 424) and non-demented controls (n = 466). AD patients were compared with non-demented control subjects using single-locus and haplotype approaches. In the whole study group, the age, sex and APOE adjusted OR for the risk of AD in C-allele carriers of the SNP rs4988 514 was 1.42 (p <0.05). Interestingly, in APOE epsilon4-allele carriers, the age and sex adjusted OR for the risk of AD in C-allele carriers of the rs4988 514 increased to 2.05 (p <0.01). Additionally, SNP rs4988514 may interact with the APOE epsilon4-allele to increase the risk of AD. Assessment of individual haplotype distributions revealed a 2-fold overrepresentation of the TCG haplotype of SNPs rs3864101, rs4988 514 and rs7624 906 in the AD APOE epsilon4-allele group (p <0.01). Conversely, a major haplotype TTG was significantly underrepresented among all the AD patients as well as APOE epsilon4-allele carrying AD patients. Thus the major haplotype TTG of somatostatin may have a protective effect against AD. This first genetic association study between somatostatin and AD indicates that genetic variations in the somatostatin gene may modify the risk for AD among Finnish AD subjects.     

Immune functions in Parkinson's disease lymphocyte subsets, concanavalin A-induced suppressor cell activity and in vitro immunoglobulin production

Immune abnormalities, including the occurrence of autoantibodies against neural structures, diminished numbers of peripheral blood lymphocytes and reduced mitogen responses have been observed in patients with Parkinson's disease. In this study, we found that among the peripheral blood mononuclear cells (PBMNC) of patients with Parkinson's disease, there is a reduced number of cells spontaneously secreting immunoglobulins (Ig). After pokeweed mitogen stimulation, PBMNCs from patients with advanced Parkinson's disease had decreased capacity to elaborate Igs in vitro. In addition, there was evidence suggesting that OKT4+ (helper/inducer) subset may be decreased in Parkinson's disease along with disordered concanavalin A-induced suppressor cell activity. The findings do not primarily suggest an autoimmune pathogenesis of Parkinson's disease. The immune changes now observed partially resemble those seen in normal ageing, though being quantitatively exaggerated in Parkinson's disease. It is suggested that immune abnormalities in Parkinson's disease may result from disordered neural-immune regulation.     

Neuroacanthocytosis masquerading as Huntington's disease: CT/MRI findings.

Neuroacanthocytosis (NA) is a rare, degenerative, presumably autosomal-recessive disorder of the nervous system presenting in adulthood and is associated with acanthocytosis of the peripheral blood. The clinical spectrum of NA shares similarities with Huntington's disease (HD), including dyskinetic choreiform movements and degeneration of the caudate nucleus. A woman presented with choreiform movements and was given a presumed diagnosis of HD. Neuroimaging studies were consistent with HD. She lacked the genetic marker for HD, and further evaluation revealed acanthocytosis of the peripheral blood. The case illustrates the similarities and differences in the clinical presentations and neuroimaging studies of these two disease entities, emphasizing the need for a careful clinical evaluation.     

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.     

Localization of mature neprilysin in lipid rafts

Alzheimer's disease (AD) is characterized by senile plaques caused by amyloid-β peptide (Aβ) accumulation. It has been reported that Aβ generation and accumulation occur in membrane microdomains, called lipid rafts, which are enriched in cholesterol and glycosphingolipids. Moreover, the ablation of cholesterol metabolism has been implicated in AD. Neprilysin (NEP), a neutral endopeptidase, is one of the major Aβ-degrading enzymes in the brain. Activation of NEP is a possible therapeutic target. However, it remains unknown whether the activity of NEP is regulated by its association with lipid rafts. Here we show that only the mature form of NEP, which has been glycosylated in the Golgi, exists in lipid rafts, where it is directly associated with phosphatidylserine. Moreover, the localization of NEP in lipid rafts is enhanced by its dimerization, as shown using the NEP E403C homodimerization mutant. However, the protease activities of the mature form of NEP, as assessed by in vitro peptide hydrolysis, did not differ between lipid rafts and nonlipid rafts. We conclude that cholesterol and other lipids regulate the localization of mature NEP to lipid rafts, where the substrate Aβ accumulates but does not modulate the protease activity of NEP.     

Somatostatin receptors: distribution in rat central nervous system and human frontal cortex

Somatostatins are a brain peptide family centered on a 14-amino acid cyclic peptide (SS-14) and a 28-amino acid N-terminally extended form (SS-28). Using radioiodinated analogs of SS-14 and SS-28, we have identified specific binding sites in rat and human brain sections that display pharmacological properties anticipated for somatostatin receptors and discrete patterns of anatomical localization. High binding densities are found in many forebrain regions, with special densities in infragranular cerebral cortical laminae in rat and human brain. In the rat, other densities lie in olfactory zones, lateral and triangular septal nuclei, the CA-1 hippocampal region, and claustrum with moderate densities in the striatum. Discrete hypothalamic areas, especially the median preoptic, paraventricular, and periventricular nuclei, display elevated binding levels, while the thalamus shows only scattered areas of modest binding. Midbrain receptor concentrations are found in portions of the periaqueductal gray, interpeduncular nucleus, and the substantia nigra. Notable pontine and medullary densities lie in the locus coeruleus, fourth ventricular floor, parabrachial, solitary, prepositus hypoglossal, dorsal column, and caudal trigeminal zones. Although the cerebellar cortex shows unimpressive densities, each of the deep cerebellar nuclei is heavily labeled. Modest spinal cord receptor densities are concentrated in the substantia gelatinosa and central cord regions. These localizations show many parallels with the distributions of SS-immunoreactive neurons, fibers, and terminals determined previously by immunohistochemistry. They provide plausible loci for several reported physiological or pharmacological activities of the SS-peptides, and may improve understanding of the role of the SS alterations described in several human neurodegenerative disorders.     

Protective Effect of Leptin and Ghrelin against Toxicity Induced by Amyloid‐β Oligomers in a Hypothalamic cell Line

In addition to cognitive decline, Alzheimer's disease (AD) patients also exhibit an unexplained weight loss that correlates with disease progression. In young and middle‐aged AD patients, large amounts of amyloid‐β (Aβ) deposits were observed in the hypothalamus, a brain region involved in the control of feeding and body weight through the action of peripheral metabolic peptides, which have recently been shown to have neuroprotective effects. Moreover, levels of peripheral metabolic peptides, such as leptin and ghrelin, are changed in AD patients. The present study aimed to investigate the role of Aβ peptide in the survival of hypothalamic cells and to explore the receptor‐mediated protective effect of leptin and ghrelin against Aβ‐induced toxicity in these cells. Using the mHypoE‐N42 cell line, we demonstrated for the first time that oligomeric Aβ is toxic to hypothalamic cells, leading to cell death. It was also demonstrated that leptin and ghrelin protect these cells against AβO‐induced cell death through the activation of the leptin and ghrelin receptors, respectively. Furthermore, ghrelin and leptin prevented superoxide production, calcium rise and mitochondrial dysfunction triggered by AβO. Taken together, these results suggest that peripheral metabolic peptides, in particular leptin and ghrelin, might be considered as preventive strategies for ameliorating hypothalamic alterations in AD.