Amyloid β precursor protein as a molecular target for amyloid β–induced neuronal degeneration in Alzheimer's disease

Bignante, Elena Anahi; Heredia, Florencia; Morfini, Gerardo; Lorenzo, Alfredo

doi:10.1016/j.neurobiolaging.2013.04.021

Cited by 40 publications

(34 citation statements)

References 237 publications

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“…It has been reported that the normal physiological function of APP may be compromised by Aβ (Bignante et al, 2013). Direct interactions between Aβ fibrils and APP were described, with Aβ acting to enhance APP multimerization, a potentially toxic mechanism (Lorenzo et al, 2000; Van Nostrand et al, 2002; Lu et al, 2003; Shaked et al, 2006; Sola Vigo et al, 2009; Kedikian et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Role of Drosophila Amyloid Precursor Protein in Memory Formation

Préat

Goguel

2016

Front. Mol. Neurosci.

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The amyloid precursor protein (APP) is a membrane protein engaged in complex proteolytic pathways. APP and its derivatives have been shown to play a central role in Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by memory decline. Despite a huge effort from the research community, the primary cause of AD remains unclear, making it crucial to better understand the physiological role of the APP pathway in brain plasticity and memory. Drosophila melanogaster is a model system well-suited to address this issue. Although relatively simple, the fly brain is highly organized, sustains several forms of learning and memory, and drives numerous complex behaviors. Importantly, molecules and mechanisms underlying memory processes are conserved from flies to mammals. The fly encodes a single non-essential APP homolog named APP-Like (APPL). Using in vivo inducible RNA interference strategies, it was shown that APPL knockdown in the mushroom bodies (MB)—the central integrative brain structure for olfactory memory—results in loss of memory. Several APPL derivatives, such as secreted and full-length membrane APPL, may play different roles in distinct types of memory phases. Furthermore, overexpression of Drosophila amyloid peptide exacerbates the memory deficit caused by APPL knockdown, thus potentiating memory decline. Data obtained in the fly support the hypothesis that APP acts as a transmembrane receptor, and that disruption of its normal function may contribute to cognitive impairment during early AD.

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Section: Discussionmentioning

confidence: 99%

Role of Drosophila Amyloid Precursor Protein in Memory Formation

Préat

Goguel

2016

Front. Mol. Neurosci.

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“…Essential for physiological brain development (neurogenesis and synaptogenesis) and plasticity [26,85]. …”

Section: Pathophysiology Genetics and Functional Brain Processing Umentioning

confidence: 99%

Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease

Chiesa

Cavedo

Lista

et al. 2017

Trends in Neurosciences

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The quest to comprehend genetic, biological, and symptomatic heterogeneity underlying Alzheimer’s disease (AD) requires a deep understanding of mechanisms affecting complex brain systems. Neuroimaging genetics is an emerging field that provides a powerful way to analyze and characterize intermediate biological phenotypes of AD. Here, we describe recent studies showing the differential effect of genetic risk factors for AD on brain functional connectivity in cognitively normal, preclinical, prodromal, and AD dementia individuals. Functional neuroimaging genetics holds particular promise for the characterization of preclinical populations; target populations for disease prevention and modification trials. To this end, we emphasize the need for a paradigm shift towards integrative disease modeling and neuroimaging biomarker-guided precision medicine for AD and other neurodegenerative diseases.

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“…Overexpression of APP has been associated with an increase in Aβ42 levels in the brains of foetuses with DS (Teller et al, 1996). Binding of aggregated Aβ to APP is likely to promote increased metabolic processing of APP through the amyloidogenic pathway, further contributing to Aβ deposition, neuritic degeneration, and synapse loss in AD (Bignante, 2013) and DS.…”

mentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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Amyloid β precursor protein as a molecular target for amyloid β–induced neuronal degeneration in Alzheimer's disease

Cited by 40 publications

References 237 publications

Role of Drosophila Amyloid Precursor Protein in Memory Formation

Role of Drosophila Amyloid Precursor Protein in Memory Formation

Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

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