Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease

Abstract

Alzheimer disease (AD) is an aging-related disorder linked to endoplasmic reticulum (ER) stress. The main pathologic feature of AD is the presence of extracellular senile plaques and intraneuronal neurofibrillary tangles (NFTs) in the brain. In neurodegenerative diseases, the unfolded protein response (UPR) induced by ER stress ensures cell survival. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against ER stress and has been implicated in the pathogenesis of AD. MANF is expressed in neurons of the brain and spinal cord. However, there have been no investigations on MANF expression in the brain of AD patients. This was addressed in the present study by immunohistochemistry, western blotting, and quantitative analyses of postmortem brain specimens. We examined the localization and expression levels of MANF in the inferior temporal gyrus of the cortex (ITGC) in AD patients (n = 5), preclinical (pre-)AD patients (n = 5), and age-matched non-dementia controls (n = 5) by double immunofluorescence labeling with antibodies against the neuron-specific nuclear protein neuronal nuclei (NeuN), ER chaperone protein 78-kDa glucose-regulated protein (GRP78), and MANF. The results showed that MANF was mainly expressed in neurons of the ITGC in all 3 groups; However, the number of MANF-positive neurons was significantly higher in pre-AD (Braak stage III/IV) and AD (Braak stage V/VI) patients than that in the control group. Thus, MANF is overexpressed in AD and pre-AD, suggesting that it can serve as a diagnostic marker for early stage disease.

The Role of the Mesencephalic Astrocyte‐Derived Neurotrophic Factor in Patients in Intensive Care Units Receiving Voriconazole Therapy

“…It is overexpressed in neurons in the brains of patients with preclinical Alzheimer's disease (pre-AD) and AD, suggesting that it can serve as a diagnostic marker for early-stage disease. 36 Restoring MANF levels in mice who are old is sufficient to reverse liver damage and inflammation. 13 Therefore, we propose that supplementation with MANF will show a protective effect in elderly patients.…”

“…MANF also appears to provide protective effects in age‐related diseases. It is overexpressed in neurons in the brains of patients with preclinical Alzheimer's disease (pre‐AD) and AD, suggesting that it can serve as a diagnostic marker for early‐stage disease 36 . Restoring MANF levels in mice who are old is sufficient to reverse liver damage and inflammation 13 .…”

MANF/EWSR1/ANXA6 pathway might as the bridge between hypolipidemia and major depressive disorder

“…MANF levels are known to be disturbed in neurodegenerative diseases [ 39 ] or ischemic stroke [ 40 ]. So far, to our knowledge, this was the first study that investigated the concentration of serum MANF in MDD patients.…”

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): An Emerging Therapeutic Target for Neurodegenerative Disorders

“…Similar to PD, clinical studies addressing the therapeutic utility of MANF in AD are sparse. Liu et al studied the distribution of MANF in the inferior temporal gyrus of the cortex (ITGC) of AD patients [ 51 ]. They found a partial co-localization of MANF and GRP78 in the ER.…”

“…They found a partial co-localization of MANF and GRP78 in the ER. Additionally, they noted a higher number of MANF-positive neurons in the ITGC of pre-AD and AD brains compared to non-AD brain samples, showing that MANF is upregulated in AD and may serve as a marker for AD [ 51 ].…”