Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology

Cai, Wei; Li, Linxi; Sang, Shaoming; Pan, Xiaoli; Zhong, Chunjiu

doi:10.1007/s12264-022-00985-9

Cited by 26 publications

(21 citation statements)

References 259 publications

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“…Research suggests that elevated Aβ damages synapses 1 , but it's crucial to highlight that most prior studies explore supraphysiological levels of exogenous Aβ, not physiological increases in endogenous Aβ. Indeed, evidence from mouse studies points to a hormetic effect of Aβ, where high levels of Aβ are synaptotoxic, but picomolar increases in Aβ often enhance synaptic function 3,[90][91][92][93][94][95][96] . Our observation that increased endogenous Aβ concentration in HBSCs increases the expression of synaptic transcripts, provides evidence that a similar hormetic role of Aβ may be present in human brain tissue.…”

Section: Discussionmentioning

confidence: 99%

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

McGeachan,

Meftah,

Taylor

et al. 2024

Preprint

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In Alzheimer’s disease, it is theorised that amyloid beta (Aβ) and tau pathology contribute to synapse loss. However, there is limited information on how endogenous levels of tau and Aβ protein relate to patient characteristics, or how manipulating physiological levels of Aβ impacts synapses, in living adult, human brain. Here, we employed live human brain slice cultures as a translational tool to assess endogenous tau and Aβ release, pathology, and response to experimental manipulation. We found that the levels of Aβ1-40and tau detected in the culture medium depend on donor age, and brain region, respectively. Pharmacologically raising physiological Aβ concentration enhanced levels of synaptic transcripts. Treatment of slices with Aβ-containing Alzheimer’s disease brain extract resulted in postsynaptic Aβ uptake and loss of presynaptic puncta. These data indicate that physiological and pathological Aβ can have opposing effects on synapses in living human brain tissue.

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Section: Discussionmentioning

confidence: 99%

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

McGeachan,

Meftah,

Taylor

et al. 2024

Preprint

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“…Neurotoxicity of the longer Aβ fragments and cell to cell seeding could also be mediated via a non-cell autonomous mechanism such as microglial activation [ 100 , 101 ]. It has been shown that reduced endogenous Aβ may also impair synaptic function [ 102 ]. Therefore, also the strongly diminished Aβ40 levels of APP Iberian could explain the negative effects of the Iberian mutation on synapse formation.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity

Schilling

Pradhan

Heesch

et al. 2023

acta neuropathol commun

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The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms.

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“…Full-length APP directly regulates metabolism in the CNS and peripheral tissue and can modulate mitochondrial functions [ 38 , 39 , 40 ]. It can be cleaved by proteases in different ways to produce a variety of short peptides, some of which, e.g., β-amyloid, possess toxic properties [ 40 , 41 ].…”

Section: Physiological Roles Of Amyloidogenic Ppsmentioning

confidence: 99%

“…Under physiological conditions, Aβ production is reportedly associated with neuronal activity [ 43 ] and regulated by the sleep/wake cycle [ 44 ]. A deficiency in endogenous Aβ causes synaptic dysfunction and cognitive defects, whereas a mild increase enhances long-term potentiation and leads to neuronal hyperexcitability [ 41 ].…”

Section: Physiological Roles Of Amyloidogenic Ppsmentioning

confidence: 99%

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era

et al. 2023

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For a long time, studies of amyloidogenic proteins and peptides (amyloidogenic PPs) have been focused basically on their harmful properties and association with diseases. A vast amount of research has investigated the structure of pathogenic amyloids forming fibrous deposits within or around cells and the mechanisms of their detrimental actions. Much less has been known about the physiologic functions and beneficial properties of amyloidogenic PPs. At the same time, amyloidogenic PPs have various useful properties. For example, they may render neurons resistant to viral infection and propagation and stimulate autophagy. We discuss here some of amyloidogenic PPs’ detrimental and beneficial properties using as examples beta-amyloid (β-amyloid), implicated in the pathogenesis of Alzheimer’s disease (AD), and α-synuclein—one of the hallmarks of Parkinson’s disease (PD). Recently amyloidogenic PPs’ antiviral and antimicrobial properties have attracted attention because of the COVID-19 pandemic and the growing threat of other viral and bacterial-induced diseases. Importantly, several COVID-19 viral proteins, e.g., spike, nucleocapsid, and envelope proteins, may become amyloidogenic after infection and combine their harmful action with the effect of endogenous APPs. A central area of current investigations is the study of the structural properties of amyloidogenic PPs, defining their beneficial and harmful properties, and identifying triggers that transform physiologically important amyloidogenic PPs into vicious substances. These directions are of paramount importance during the current SARS-CoV-2 global health crisis.

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Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology

Cited by 26 publications

References 259 publications

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era

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