Cholinergic‐associated loss of hnRNP‐A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice

Berson, Amit; Barbash, Shahar; Shaltiel, Galit; Goll, Yael; Hanin, Geula; Greenberg, David; Ketzef, Maya; Becker, Albert; Friedman, Alon; Soreq, Hermona

doi:10.1002/emmm.201100995

Cited by 140 publications

(138 citation statements)

References 59 publications

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“…S5A). Other RNA splicing factors, such as hnRNP A/B, recently suggested as a dysfunctional splicing factor in AD (38), and serine/arginine repetitive matrix protein 2 (SRRM2), did not demonstrate tangle-like aggregates, suggesting that this may be a U1 snRNP-specific process (Fig. S4 A-D).…”

Section: Resultsmentioning

confidence: 88%

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Bai

Hales

Chen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

282

380

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Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer's disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc boxdependent-interacting protein 1, clusterin, and presenilin-1. U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein.Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.proteomics | liquid chromatography-tandem mass spectrometry | U1A | RNA-seq | premature cleavage and polyadenylation

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Section: Resultsmentioning

confidence: 88%

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Bai

Hales

Chen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

282

380

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show abstract

“…Interestingly, deficiency in cholinergic signaling has recently been shown to decrease cortical expression of the heterogeneous nuclear ribonucleoproteins hnRNP A/B family. Reduced expression of these hnRNA splicing factors induces alternative splicing impairments, dendrite loss in primary neurons, and cognitive impairments in mice (38). Further studies will be necessary to investigate whether expression of hnRNA splicing factors is affected in VAChT-deficient mice and contributes to cognitive dysfunction.…”

Section: Forebrain Cholinergic Tone Is Involved In Spontaneous Locomomentioning

confidence: 99%

Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation

Martyn¹,

Jaeger

Magalhães³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define which cholinergic-dependent behaviors could be improved pharmacologically. Here we investigate the contributions of forebrain ACh on hippocampal synaptic plasticity and cognitive behavior by selective elimination of the vesicular ACh transporter, which interferes with synaptic storage and release of ACh. We show that elimination of vesicular ACh transporter in the hippocampus results in deficits in long-term potentiation and causes selective deficits in spatial memory. Moreover, decreased cholinergic tone in the forebrain is linked to hyperactivity, without changes in anxiety or depression-related behavior. These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy.Alzheimer's disease | Morris water maze | synaptic vesicle | Barnes maze T he mechanisms that underlie the formation of hippocampaldependent spatial memory have been broadly explored (1). However, the neurochemical basis underlying changes in the strength of synaptic connections necessary for memories to persist is still not precisely understood. In the case of the hippocampus, mechanisms for memory processing include mRNA-dependent (2) and mammalian target of rapamycin (mTOR)-mediated protein synthesis (3) as well as a sequence of biochemical events shared with or closely similar to that of long-term potentiation (LTP) (2). Indeed, the consolidation of two different aversive tasks (4) and of spatial recognition memory (5) is accompanied by LTP of the CA3-CA1 synapse and can be occluded by a preceding LTP.The basal forebrain cholinergic system, which innervates the hippocampus and cortex, has been suggested to modulate LTP in the hippocampus (6-9) and has been implicated in many forms of behavior (10). In addition, spatial memory has also been suggested to depend on cholinergic activity (10), although there are numerous controversies surrounding which behaviors acetylcholine (ACh) regulates (11, 12). Moreover, in few studies cholinergic denervation did not affect expression of LTP (13). Understanding the precise roles of ACh in learning and memory is of importance because in different types of dementia cholinergic function is decreased (14), and manipulations that boost ACh levels at synapses are used a...

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“…Distinctive patterns of alternative splicing and promoter use were discovered in LOAD brain tissue through comparing the transcriptome profiles of the frontal, temporal and parietal lobes of AD patients with controls [33,34]. Additionally, small nuclear and heterogeneous nuclear ribonucleoproteins have been shown to be disrupted in LOAD [35,36]. Therefore the role of splicing in LOAD disease pathology should not be ignored.…”

Section: Discussionmentioning

confidence: 99%

Investigating Splicing Variants Uncovered by Next-Generation Sequencing the Alzheimer’s Disease Candidate Genes, CLU, PICALM, CR1, ABCA7, BIN1, the MS4A Locus, CD2AP, EPHA1 and CD33

Clement¹,

Braae²,

Turton³

et al. 2016

J Alzheimers Dis Parkinsonism

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Cholinergic‐associated loss of hnRNP‐A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice

Cited by 140 publications

References 59 publications

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation

Investigating Splicing Variants Uncovered by Next-Generation Sequencing the Alzheimer’s Disease Candidate Genes, CLU, PICALM, CR1, ABCA7, BIN1, the MS4A Locus, CD2AP, EPHA1 and CD33

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