Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony

doi:10.1016/j.tins.2017.04.002

Trends in Neurosciences

Volume 40, Issue 6, June 2017, Pages 347-357

https://doi.org/10.1016/j.tins.2017.04.002 Get rights and content

Trends

AD afflicts over 35 million people throughout the world, including 5.4 million individuals in the USA alone, with a new case developing every 66 sec.

Synaptic loss is the best predictor of the clinical symptoms of AD and the mechanisms by which this deficit occurs is an intense area of investigation.

Aβ oligomers have been classified as types 1 and 2; the latter appears to contribute to synaptotoxicity.

Tau can translocate from axons to the somatodendritic compartment and into spines, where it might interfere with synaptic function.

Significant advances have been made during the past years regarding the actions, interactions, and pathological role of Aβ and tau in synapses, yet many different questions for a better understanding of how Aβ and tau are connected to impair the synaptic function remain.

Alzheimer’s disease (AD) is characterized by memory loss, cognitive decline, and devastating neurodegeneration, not only as a result of the extracellular accumulation of beta-amyloid peptide (Aβ) and intracellular accumulation of tau, but also as a consequence of the dysfunction and loss of synapses. Although significant advances have been made in our understanding of the relationship of the pathological role of Aβ and tau in synapse dysfunction, several questions remain as to how Aβ and tau interdependently cause impairments in synaptic function in AD. Overall, more insight into these questions should enable researchers in this field to develop novel therapeutic targets to mitigate or delay the cognitive deficits associated with this devastating disease.

Section snippets

Synapses Disruption As a Key Factor for Alzheimer’s Disease

AD is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. Currently, AD afflicts over 35 million people throughout the world, including 5.4 million individuals in the USA alone, with a new case developing every 66 sec. AD is the sixth leading cause of death in the USA, killing more people than breast and prostate cancer combined 1, 2. Given that there are no treatments to prevent or reverse AD, in the absence of new breakthroughs, the

New Insights into an Old Friend: Amyloid-Beta Species and the Synaptic Impairment

Aβ is a peptide produced through the sequential cleavage of amyloid precursor protein (APP), with the 40- and 42-amino acid residue peptides being the predominant species. When APP is cleaved by α-secretase, its large amino (N)-terminal ectodomain is secreted into the extracellular medium. The resulting fragment is retained in the membrane and then is either cleaved by β- and γ-secretases to produce soluble Aβ or coalesces under a beta-sheet conformation to form toxic, soluble,

Concluding Remarks

In summary, significant advances in our understanding of how tau impacts synaptic function and is related to the pathological role of Aβ in synapses have been made over recent years. Yet, many questions remain that need to be addressed if we are to better understand how these fellow travelers (Aβ and tau) are connected to impair synaptic function. For example, due to the diversity and complexity of Aβ aggregates, it is crucial to investigate the pathological role of these different Aβ

Acknowledgments

The authors are supported by grants from the Alzheimer’s Association [NIRG-15-363477 (D.B.V.) and #AARF-16-440760 (S.F.)], The Larry L. Hillblom Foundation [#2013-A-016-FEL (D.B.V.) and 2016-A-016-FEL (A.C.M.)], the National Institute of Health (NIH) [NIH/NIA AG027544, AG00538, and AG054884 (F.M.L.)], and the BrightFocus Foundation [grant A2015535S] (F.M.L.). The authors would like to acknowledge the use of Mind the Graph for the design of the figures.

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Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by cognitive dysfunction. The connection between neuroinflammation and abnormal synaptic function in AD is recognized, but the underlying mechanisms remain unclear. In this study, we utilized a mouse model of AD, FAD^4T mice aged 6–7 months, to investigate the molecular changes affecting cognitive impairment. Behavior tests showed that FAD^4T mice exhibited impaired spatial memory compared with their wild-type littermates. Immunofluorescence staining revealed the presence of Aβ plaques and abnormal glial cell activation as well as changes in microglial morphology in the cortex and hippocampus of FAD^4T mice. Synaptic function was impaired in FAD^4T mice. Patch clamp recordings of hippocampal neurons revealed reduced amplitude of miniature excitatory postsynaptic currents. Additionally, Golgi staining showed decreased dendritic spine density in the cortex and hippocampus of FAD^4T mice, indicating aberrant synapse morphology. Moreover, hippocampal PSD-95 and NMDAR1 protein levels decreased in FAD^4T mice. RNA-seq analysis revealed elevated expression of immune system and proinflammatory genes, including increased C1qA protein and mRNA levels, as well as higher expression of TNF-α and IL-18. Taken together, our findings suggest that excessive microglia activation mediated by complement factor C1qA may contribute to aberrant synaptic pruning, resulting in synapse loss and disrupted synaptic transmission, ultimately leading to AD pathogenesis and behavioral impairments in the FAD^4T mouse model. Our study provides valuable insights into the underlying mechanisms of cognitive impairments and preliminarily explores a potentially effective treatment approach targeting on C1qA for AD.
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Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer’s disease (AD) pathology. Akt/mTOR signaling pathways, activated by external inputs, enable new protein synthesis at the synapse and synaptic plasticity. The molecular mechanisms impeding new protein synthesis at the synapse in AD pathogenesis remain elusive. Here, we aimed to understand the molecular mechanisms prior to the manifestation of histopathological hallmarks by characterizing Akt1/mTOR signaling cascades and new protein synthesis in the hippocampus of WT and amyloid precursor protein/presenilin-1 (APP/PS1) male mice. Intriguingly, compared to those in WT mice, we found significant decreases in pAkt1, pGSK3β, pmTOR, pS6 ribosomal protein, and p4E-BP1 levels in both post nuclear supernatant and synaptosomes isolated from the hippocampus of one-month-old (presymptomatic) APP/PS1 mice. In synaptoneurosomes prepared from the hippocampus of presymptomatic APP/PS1 mice, activity-dependent protein synthesis at the synapse was impaired and this deficit was sustained in young adults. In hippocampal neurons from C57BL/6 mice, downregulation of Akt1 precluded synaptic activity–dependent protein synthesis at the dendrites but not in the soma. In three-month-old APP/PS1 mice, Akt activator (SC79) administration restored deficits in memory recall and activity-dependent synaptic protein synthesis. C57BL/6 mice administered with an Akt inhibitor (MK2206) resulted in memory recall deficits compared to those treated with vehicle. We conclude that dysregulation of Akt1/mTOR and its downstream signaling molecules in the hippocampus contribute to memory recall deficits and loss of activity-dependent synaptic protein synthesis. In AD mice, however, Akt activation ameliorates deficits in memory recall and activity-dependent synaptic protein synthesis.
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Trends in Neurosciences

ReviewSynaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony

Trends

Section snippets

Synapses Disruption As a Key Factor for Alzheimer’s Disease

New Insights into an Old Friend: Amyloid-Beta Species and the Synaptic Impairment

Concluding Remarks

Acknowledgments

Arch. Med. Res.

Neurobiol. Learn. Mem.

Am. J. Pathol.

Neuron

J. Biol. Chem.

Biochem. Pharmacol.

Brain Res. Bull.

Am. J. Pathol.

Neuropharmacology

J. Biol. Chem.

Structure

Neurobiol. Dis.

Trends Neurosci.

J. Biol. Chem.

Curr. Opin. Neurobiol.

J. Biol. Chem.

Neuroscience

Am. J. Pathol.

Neuron

Neurobiol. Aging

Biochim. Biophys. Acta

Biochem. Pharmacol.

Neuron

Neuron

2015 Alzheimer’s disease facts and figures

Alzheimers Dement.

Soluble Abeta oligomer production and toxicity

J. Neurochem.

Failed Alzheimer’s trial does not kill leading theory of disease

Nature

Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease

Acta Neuropathol. Commun.

The amyloid hypothesis of Alzheimer’s disease at 25 years

EMBO Mol. Med.

Alzheimer’s disease: the challenge of the second century

Sci. Transl. Med.

The case for rejecting the amyloid cascade hypothesis

Nat. Neurosci.

Picomolar amyloid-beta peptides enhance spontaneous astrocyte calcium transients

J. Alzheimers Dis.

Hormetic effect of amyloid-beta peptide in synaptic plasticity and memory

Neurobiol. Aging

A novel mechanism for cyclic adenosine monophosphate-mediated memory formation: role of amyloid beta

Ann. Neurol.

A Luminex assay detects amyloid beta oligomers in Alzheimer’s disease cerebrospinal fluid

PLoS One

Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta

Brain

The essential role of soluble abeta oligomers in Alzheimer’s disease

Mol. Neurobiol.

Memantine rescues transient cognitive impairment caused by high-molecular-weight abeta oligomers but not the persistent impairment induced by low-molecular-weight oligomers

J. Neurosci.

Large soluble oligomers of amyloid beta-protein from alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate

J. Neurosci.

Non-fibrillar oligomeric amyloid-beta within synapses

J. Alzheimers Dis.

Abeta42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-beta42 species and protects synaptic structure and function

Sci. Rep.

beta-Amyloid oligomers in aging and Alzheimer’s disease

Front. Aging Neurosci.

Correlation of specific amyloid-beta oligomers with tau in cerebrospinal fluid from cognitively normal older adults

JAMA Neurol.

Brain amyloid-beta oligomers in ageing and Alzheimer’s disease

Brain

Neuronal amyloid-beta accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease

Brain

Accumulation of intraneuronal beta-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses

PLoS One

Intracellular Abeta pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study

Acta Neuropathol. Commun.

AbetaPP accumulation and/or intraneuronal amyloid-beta accumulation? The 3xTg-AD mouse model revisited

J. Alzheimers Dis.

Review
Synaptic Impairment in Alzheimer’s Disease: A Dysregulated Symphony