Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68: 1501-1508
University of Pittsburgh, Pittsburgh, Pennsylvania, United States Neurology
(Impact Factor: 8.29).
06/2007; 68(18):1501-8. DOI: 10.1212/01.wnl.0000260698.46517.8f
To evaluate the total number of synapses in the stratum radiatum (str rad) of the human hippocampal CA1 subfield in individuals with mild Alzheimer disease (mAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI) and determine if synapse loss is an early event in the progression of the disease.
Short postmortem autopsy tissue was obtained, and an unbiased stereologic sampling scheme coupled with transmission electron microscopy was used to directly visualize synaptic contacts.
Individuals with mAD had fewer synapses (55%) than the other two diagnostic groups. Individuals with MCI had a mean synaptic value that was 18% lower than the NCI group mean. The total number of synapses showed a correlation with several cognitive tests including those involving both immediate and delayed recall. Total synaptic numbers showed no relationship to the subject's Braak stage or to APOE genotype. The volume of the str rad was reduced in mAD vs the other two diagnostic groups that were not different from each other.
These results strongly support the concept that synapse loss is a structural correlate involved very early in cognitive decline in mild Alzheimer disease (mAD) and supports mild cognitive impairment as a transitional stage between mAD and no cognitive impairment.
Available from: Arnaldo Parra-Damas
- "t al . , 1991 ) . Synapse loss affects different neuronal populations and neurotransmitter systems in brains of AD subjects ( Masliah et al . , 1990 ; Scheff et al . , 1990 , 2007 ) . Individuals with amnestic MCI and AD have significantly fewer synapses and synaptic proteins in CA1 hippocampus and inferior temporal and posterior cingulate gyrus ( Scheff et al . , 2007 ) . Accumulation of soluble toxic forms of tau and Aβ at synapses may be a crucial event leading to synapse loss and neurodegeneration ( Spires - Jones and Hyman , 2014 ) . Thus , loss of dendritic spines in cortical pyramidal neurons parallels tau phosphorylation during aging ( Merino - Serrais et al . , 2013 ) , whereas soluble Aβ pep"
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ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders.
Available from: Santosh Jadhav
- "Neurofibrillary tangles, amyloid plaques, neuronal loss and synaptic failure represent the major hallmarks of Alzheimer's disease (AD; Wischik et al., 1988; Rinne et al., 1989; DeKosky and Scheff, 1990; Cras et al., 1991; West et al., 1994; Coleman and Yao, 2003). Synaptic deficits occur very early in AD and correlate well with the severity of dementia in AD patients (Davies et al., 1987; Masliah et al., 2001; Scheff et al., 2007). "
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ABSTRACT: Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer's disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre-and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.
Available from: Marie-Ève Tremblay
- "The lack of GPR84 increases b-amyloid-induced dendritic degeneration It is known that b-amyloid induces dendritic degeneration in APP/PS1 mice (Tsai et al., 2004; Dikranian et al., 2012) and AD brains (Masliah et al., 1994; Scheff et al., 2007), but whether microglia exert a protective or deleterious role in this phenomenon is still a matter of speculation (Siskova and Tremblay, 2013). To assess whether microglial GPR84 influences dendritic degeneration , we examined the hippocampal CA1 stratum radiatum of Fig. 2. Clinical assessment of GPR84 knockout and wild-type mice in three disease models. "
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ABSTRACT: Microglia surrounds the amyloid plaques that form in the brains of patients with Alzheimer's disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, i.e., experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline.
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