Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in cerebrospinal fluid (CSF), and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared to age-matched control cases, indicate a physiological upregulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD.

Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease, which likely plays a critical role in the pathogenesis of disease. Increasing evidence suggests abnormal mitochondrial dynamics as important underlying mechanisms. In this study, we characterized marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of Alzheimer's disease mouse model CRND8 as early as 3 months of age before the accumulation of amyloid pathology. To establish the pathogenic significance of these abnormalities, we inhibited mitochondrial fragmentation by the treatment of mitochondrial division inhibitor 1 (mdivi-1), a mitochondrial fission inhibitor. Mdivi-1 treatment could rescue both mitochondrial fragmentation and distribution deficits and improve mitochondrial function in the CRND8 neurons both in vitro and in vivo. More importantly, the amelioration of mitochondrial dynamic deficits by mdivi-1 treatment markedly decreased extracellular amyloid deposition and Ab 1-42 /Ab 1-40 ratio, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters. Our findings support the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and Alzheimer's diseaserelated pathological and cognitive impairments in vivo and indicate the potential value of restoration of mitochondrial dynamics as an innovative therapeutic strategy for Alzheimer's disease. e.g. mitofusins (Mfn1 and Mfn2) and OPA1 for fusion and dynamin-like protein 1 (DLP1) for fission with the assistance of other factors in mammalian cells (2). Mitochondrial dynamics is critical for maintaining the proper ultrastructure and † These authors contributed equally to this work.

At autopsy, the time that has elapsed since the time of death is routinely documented and noted as the postmortem interval (PMI). The PMI of human tissue samples is a parameter often reported in research studies and comparable PMI is preferred when comparing different populations, i.e., disease versus control patients. In theory, a short PMI may alleviate non-experimental protein denaturation, enzyme activity, and other chemical changes such as the pH, which could affect protein and nucleic acid integrity. Previous studies have compared PMI en masse by looking at many different individual cases each with one unique PMI, which may be affected by individual variance. To overcome this obstacle, in this study human hippocampal segments from the same individuals were sampled at different time points after autopsy creating a series of PMIs for each case. Frozen and fixed tissue was then examined by Western blot, RT-PCR, and immunohistochemistry to evaluate the effect of extended PMI on proteins, nucleic acids, and tissue morphology. In our results, immunostaining profiles for most proteins remained unchanged even after PMI of over 50 h, yet by Western blot distinctive degradation patterns were observed in different protein species. Finally, RNA integrity was lower after extended PMI; however, RNA preservation was variable among cases suggesting antemortem factors may play a larger role than PMI in protein and nucleic acid integrity.

BackgroundMitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease.MethodsTo examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD.ResultsElectron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size.ConclusionsOverall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0238-8) contains supplementary material, which is available to authorized users.