Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons

Ovsepian, Saak V.; Antyborzec, Inga; O’Leary, Valerie B.; Záborszky, László; Herms, Jochen; Dolly, J. Oliver

doi:10.1007/s00429-013-0583-x

Cited by 32 publications

(23 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the over-activation of p75 signaling is linked to cholinergic dysregulation in AD and Aβ-reduced choline uptake [65], it is conceivable that extracellular oligomeric Aβ may produce aberrant CHT trafficking by activating p75-mediated downstream signaling pathways and disrupt cortical cholinergic transmission and attentional capacities. Recent evidence suggests that the Aβ peptide could be internalized into the BF cholinergic neurons via a p75 receptor-dependent mechanism [66]. Thus, we could also not rule out that soluble Aβ-mediated disruption of choline transport and CHT function result from intracellular accumulation of these synaptotoxic oligomers.…”

Section: Discussionmentioning

confidence: 81%

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

Parikh

Bernard

Naughton

et al. 2014

Behavioural Brain Research

View full text Add to dashboard Cite

Substantial evidence suggests that cerebral deposition of the neurotoxic fibrillar form of amyloid precursor protein, β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease (AD). Yet, many aspects of AD pathology including the cognitive symptoms and selective vulnerability of cortically-projecting basal forebrain (BF) cholinergic neurons are not well explained by this hypothesis. Specifically, it is not clear why cognitive decline appears early when the loss of BF cholinergic neurons and plaque deposition are manifested late in AD. Soluble oligomeric forms of Aβ are proposed to appear early in the pathology and to be better predictors of synaptic loss and cognitive deficits. The present study was designed to examine the impact of Aβ oligomers on attentional functions and presynaptic cholinergic transmission in young and aged rats. Chronic intracranial infusions of Aβ oligomers produced subtle decrements in the ability of rats to sustain attentional performance with time on task, irrespective of the age of the animals. However, Aβ oligomers produced robust detrimental effects on performance under conditions of enhanced attentional load in aged animals. In vivo electrochemical recordings show reduced depolarization-evoked cholinergic signals in Aβ-infused aged rats. Moreover, soluble Aβ disrupted the capacity of cholinergic synapses to clear exogenous choline from the extracellular space in both young and aged rats, reflecting impairments in the choline transport process that is critical for acetylcholine (ACh) synthesis and release. Although aging per se reduced the cross-sectional area of BF cholinergic neurons and presynaptic cholinergic proteins in the cortex, attentional performance and ACh release remained unaffected in aged rats infused with the control peptide. Taken together, these data suggest that soluble Aβ may marginally influence attentional functions at young ages primarily by interfering with the choline uptake processes. However, age-related weakening of the cholinergic system may synergistically interact with these disruptive presynaptic mechanisms to make this neurotransmitter system vulnerable to the toxic effects of oligomeric Aβ in robustly impeding attentional capacities.

show abstract

Section: Discussionmentioning

confidence: 81%

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

Parikh

Bernard

Naughton

et al. 2014

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…Because p75 NTR was implicated in the uptake and retrograde transport of tetanus toxin and its H C fragment in motor neurons [63,64], we reasoned that the same mechanism could also be useful for vector targeting the BFCNs. After all, p75 NTR is strongly enriched in BFCNs in the adult brain, and targeting of cholinergic cells by small peptides or fluorescence probes linked to IgG 192 has been utilized for their labeling and destruction in vivo [22,27,29,30,32,65]. Our data show that conjugation of vectors with antip75 NTR antibody does, indeed, enable targeted expression of GFP-encoding vectors in BFCNs in adult rat brain.…”

Section: Discussionmentioning

confidence: 71%

“…The effectiveness of conjugation was verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting (12% polyacrylamide gels). Targeted material was tested for infectivity in rat primary neuronal cultures (2 μl; 9.0 × 10 6 IUs/ml), as specified [31,32].…”

Section: Targeting Lentiviral Vectorsmentioning

confidence: 99%

Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain

et al. 2016

Self Cite

View full text Add to dashboard Cite

Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal types in Alzheimer's disease (AD), with their extensive loss documented at late stages of the pathology. While discriminatory provision of neuroprotective agents and trophic factors to these cells is thought to be of substantial therapeutic potential, the intricate topography and structure of the forebrain cholinergic system imposes a major challenge. To overcome this, we took advantage of the physiological enrichment of BFCNs with a low-affinity p75 neurotrophin receptor (p75 NTR ) for their targeting by lentiviral vectors within the intact brain of adult rat. Herein, a method is described that affords selective and effective transduction of BFCNs with a green fluorescence protein (GFP) reporter, which combines streptavidinbiotin technology with anti-p75 NTR antibody-coated lentiviral vectors. Specific GFP expression in cholinergic neurons was attained in the medial septum and nuclei of the diagonal band Broca after a single intraventricular administration of such targeted vectors. Bioelectrical activity of GFP-labeled neurons was proven to be unchanged. Thus, proof of principle is obtained for the utility of the lowaffinity p75 NTR for targeted transduction of vectors to BFCNs in vivo.

show abstract

“…The results are presented as mean ± SEM. Asterisks indicate a sta tistically significant difference in neuronal density vs. non immunized OBX animals: *p < 0.05; **p < 0.01; ***p < 0.001. mechanisms mediating the loss of neurons is the abil ity of βА, via the formation of a complex with p75, to initiate endocytosis and to move retrogradely along the axons of cholinergic neurons from the neocortex to the cells of the basal forebrain complex, causing their death and acute deficiency of the acetylcholin ergic system, which is accompanied by the memory loss in AD [20]. The increased number of p75 recep tors in the hippocampus and the correlation with neu ronal death has been observed in the brain of trans genic animals and in AD patients [21].…”

Section: Resultsmentioning

confidence: 99%

Structure–Function mapping of the extracellular part of neurotrophin receptor P75

Бобкова

Medvinskaya

Nesterova

et al. 2015

Biochem. Moscow Suppl. Ser. A

View full text Add to dashboard Cite

Receptor p75 is a classical membrane receptor, which consists of an extracellular region, a trans membrane region, and an intracellular C terminus death domain. p75 is involved in the activation of neu rotrophic factors and plays an essential role in the regulation of cell functions such as proliferation, differen tiation, synaptogenesis, neuronal plasticity, and survival or apoptosis. It is supposed that p75 accelerates the positive effects of neurotrophins being a part of the complex with the Trk receptor; however, in the absence of Trk receptors, the interaction between p75 and neurotrophins leads to cell apoptosis. The interest in the p75 receptor has increased dramatically in the past few years, as it has been shown that p75 may play a crucial role in the genesis of neurodegenerative disorders, in particular, Alzheimer's disease. The interaction between p75 and β amyloid leads to neuronal death in the brain. Identification of the p75 regions involved in the develop ment of pathology is of great importance for understanding the mechanisms of Alzheimer's disease and for creating targeted therapeutic agents for this disorder. In the present work, immunological approaches have been used for structure function mapping of the extracellular domain of the p75 receptor during the devel opment of a neurodegenerative process in olfactory bulbectomized animals. The nine extracellular regions selected on the basis of X ray structure analysis of p75 molecule hypothetically could include β amyloid binding sites and participate in the progression of pathology. Peptides with the amino acid sequences analo gous to the selected regions were synthesized. Immunization with such fragments conjugated with hemocy anin induced the formation of antipeptide antibodies in experimental animals. However, only immunization with fragment (167-176) prevented the memory loss and neuronal death in the cortex and hippocampus of bulbectomized mice. This fragment had no effect on sham operated mice. The results indicate that fragment (167-176) of the p75 sequence deserves further research as a potential basis of the targeted immunotherapy of Alzheimer's disease.

show abstract

Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons

Cited by 32 publications

References 79 publications

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

Interactions between Aβ oligomers and presynaptic cholinergic signaling: Age-dependent effects on attentional capacities

Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain

Structure–Function mapping of the extracellular part of neurotrophin receptor P75

Contact Info

Product

Resources

About