A novel process driving Alzheimer's disease validated in a mouse model: Therapeutic potential

Greenfield, Susan; Cole, Gregory M.; Coen, Clive W.; Frautschy, Sally A.; Singh, Ram Pyare; Mekkittikul, Marisa; García-Ratés, Sara; Morrill, Paul; Hollings, Owen; Passmore, Matt; Hasan, Sibah; Carty, Nikisha; Bison, Silvia; Piccoli, Laura; Carletti, Renzo; Tacconi, Stefano; Chalidou, Anna; Pedercini, Matthew; Kröcher, Tim; Astner, Hubert; Gerrard, Philip

doi:10.1002/trc2.12274

Cited by 14 publications

(29 citation statements)

References 44 publications

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“…In relation to melatonin, it has been evaluated in clinical assays related to cranial nerve diseases, multiple sclerosis, epilepsy, sleep disorders, spinal cord injuries, migraine, trauma brain injury, dementia, Huntington, Alzheimer and Parkinson Diseases [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 ]. Of note, some of these diseases have also been studied in experimental models, evaluating the neuroprotective effect of these compounds mainly by their antioxidant and anti-inflammatory properties [ 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 ]. Moreover, the effects of quercetin, melatonin and curcumin have been explored in obese patients in different studies, but they have not proposed gliosis as an important comorbidity [ 2...…”

Section: Protective Role Of Antioxidants In Gliosismentioning

confidence: 99%

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

et al. 2022

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Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients. Aim: Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation. Method: Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management. Conclusion: Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration.

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Section: Protective Role Of Antioxidants In Gliosismentioning

confidence: 99%

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

et al. 2022

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“…We have previously reported the presence of AChE in the pars compacta, pars reticulata and extracellular space of the SN at light- and electron-microscopic levels [ 44 ]. The present immunohistochemical studies used a polyclonal antibody against T14 that requires an exposed COOH-terminal lysine, thereby precluding the detection of AChE, the parent molecule, or amyloid, with which T14 has a partial sequence homology [ 35 , 42 ]. Accordingly, we have identified free T14 in pars compacta neurons of the mouse SN; these were shown to be dopamine neurons by the colocalization of tyrosine hydroxylase.…”

Section: Discussionmentioning

confidence: 99%

“…T30 is a 30-mer peptide from the C-terminus of AChE; it includes T14 as the active component and is more stable than the smaller peptide in solution [ 31 ]. T14 and T30 act via alpha-7 receptors [ 30 , 31 ], enhancing calcium entry through an allosteric site [ 30 ] and triggering the accumulation of phosphorylated Tau and amyloid beta [ 35 , 42 ]. Previous studies using various experimental preparations have demonstrated that the binding of T14 or T30 to alpha-7 receptors can be blocked by NBP14, a cyclized variant that displaces the peptide from its receptor [ 33 , 35 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…We have now investigated the effects of T30 on neuronal activity in the SN. Given that a cyclic form of the T14 peptide, NBP14, has been shown to block the actions of T14 in vitro [ 35 ], ex vivo [ 41 ] and in vivo [ 42 ], it was important to examine whether this antagonist may be of benefit under conditions in which excess T14 is applied to the SN in rat brain slices. Since T14 binds to alpha-7 receptors, we also tested its bioactivity in the striatum, a site that lacks this cholinergic receptor subtype [ 43 ] in contrast to the SN, where it is plentiful [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…The SN shows significant neuronal loss in Parkinson’s and Alzheimer’s disease [ 29 , 33 , 34 ]. Given the evidence that T14 acts as a signaling molecule in cascades that drive neurodegeneration [ 42 ], the present research was undertaken to investigate this peptide within the SN and explore the therapeutic potential of its antagonist NBP14.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease

Greenfield

Ferrati

Coen

et al. 2022

IJMS

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The substantia nigra is generally considered to show significant cell loss not only in Parkinson’s but also in Alzheimer’s disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer’s pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.

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Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

Garcia Ratés,

García‐Ayllón,

Falgàs

et al. 2024

Alzheimer's & Dementia

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This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little‐known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre‐symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p‐Tau and β‐amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of β‐amyloid, and restores cognitive function to that of wild‐type counterparts. Any diagnostic and/or therapeutic strategy based on T14‐NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much‐needed fresh insights into the progression of cell loss underlying AD.Highlights The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early‐stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

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A novel process driving Alzheimer's disease validated in a mouse model: Therapeutic potential

Cited by 14 publications

References 44 publications

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease

Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

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