DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 27: 457-464

Department of Neurology, Lexington Veterans Administration, Medical Center, KY.
Annals of Neurology (Impact Factor: 9.98). 05/1990; 27(5):457-64. DOI: 10.1002/ana.410270502
Source: PubMed


Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)

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    • "Histopathologic hallmarks of AD are represented by (i) focal extracellular deposits of fibrillar b-amyloid (Ab), also known as senile or neuritic plaques, and (ii) intraneuronal accumulation of neurofibrillary tangles composed of filamentous aggregates of hyperphosphorylated Tau protein (Selkoe, 2001). The degeneration and loss of synapses precedes neuronal death (DeKosky and Scheff, 1990; Scheff et al., 1991) and may account for early cognitive impairment. It is believed that neurodegeneration occurs gradually and dementia represents the end stage of accumulating pathologic changes that may start to develop decade(s) before the onset of the earliest clinical symptoms (Jack et al., 2010). "
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    ABSTRACT: In the brain, astrocytes provide metabolic and trophic support to neurones. Failure in executing astroglial homeostatic functions may contribute to the initiation and propagation of diseases, including Alzheimer disease (AD), characterized by a progressive loss of neurones over years. Here, we examined whether astrocytes from a mice model of AD isolated in the presymptomatic phase of the disease exhibit alterations in vesicle traffic, vesicular peptide release and purinergic calcium signaling. In cultured astrocytes isolated from a newborn wild-type (wt) and 3xTg-AD mouse, secretory vesicles and acidic endosomes/lysosomes were labeled by transfection with plasmid encoding atrial natriuretic peptide tagged with mutant green fluorescent protein (ANP.emd) and by LysoTracker, respectively. The intracellular Ca(2+) concentration ([Ca(2+) ]i ) was monitored with Fluo-2 and visualized by confocal microscopy. In comparison with controls, spontaneous mobility of ANP- and LysoTracker-labeled vesicles was diminished in 3xTg-AD astrocytes; the track length (TL), maximal displacement (MD) and directionality index (DI) were all reduced in peptidergic vesicles and in endosomes/lysosomes (P < 0.001), as was the ATP-evoked attenuation of vesicle mobility. Similar impairment of peptidergic vesicle trafficking was observed in wt rat astrocytes transfected to express mutated presenilin 1 (PS1M146V ). The ATP-evoked ANP discharge from single vesicles was less efficient in 3xTg-AD and PS1M146V -expressing astrocytes than in respective wt controls (P < 0.05). Purinergic stimulation evoked biphasic and oscillatory [Ca(2+) ]i responses; the latter were less frequent (P < 0.001) in 3xTg-AD astrocytes. Expression of PS1M146V in astrocytes impairs vesicle dynamics and reduces evoked secretion of the signaling molecule ANP; both may contribute to the development of AD. GLIA 2015.
    Glia 10/2015; DOI:10.1002/glia.22931 · 6.03 Impact Factor
    • "We chose BA7 because it is an area of parietal cortex that we have previously studied intensively for its BDNF expression and regulation (Garzon et al., 2002; Holsinger et al., 2000; Michalski and Fahnestock, 2003; Peng et al., 2005), and it is an area known to be severely affected in AD (Bruner and Jacobs, 2013). We also examined some of these targets and correlations in prefrontal cortex (Brodmann area 9), another area severely affected in AD (DeKosky and Scheff, 1990). "
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    ABSTRACT: Factors associated with maintaining good cognition into old age are unclear. Decreased brain-derived neurotrophic factor (BDNF) contributes to memory loss in Alzheimer's disease (AD), and soluble assemblies of amyloid-beta (Aβ) and tau contribute to neurodegeneration. However, it is unknown whether AD-type neuropathology, soluble Aβ and tau, or levels of BDNF and its receptor tropomyosin-related kinase B (TrkB) correlate with dementia in the oldest-old. We examined these targets in postmortem Brodmann's areas 7 and 9 (BA7 and BA9) in 4 groups of subjects >90 years old: (1) no dementia/no AD pathology, (2) no dementia/AD pathology, (3) dementia/no AD pathology, (4) dementia/AD pathology. In BA7, BDNF messenger RNA correlated with Mini-Mental State Examination scores and was decreased in demented versus nondemented subjects, regardless of pathology. Soluble Aβ42 was increased in both groups with AD pathology, demented or not, compared to no dementia/no AD pathology subjects. Groups did not differ in TrkB isoform levels or in levels of total soluble tau, individual tau isoforms, threonine-181 tau phosphorylation, or ratio of phosphorylated 3R-4R isoforms. In BA9, soluble Aβ42 correlated with Mini-Mental State Examination scores and with BDNF messenger RNA expression. Thus, soluble Aβ42 and BDNF, but not TrkB or soluble tau, correlate with dementia in the oldest-old.
    Neurobiology of aging 09/2015; DOI:10.1016/j.neurobiolaging.2015.08.022 · 5.01 Impact Factor
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    • "It is pathologically characterized by the accumulation of amyloid b (Ab) in senile plaques and phosphorylated tau (p-Tau) in neurofibrillary tangles (NFTs). In addition, a remarkable loss of neurons and synapses is also observed in AD [1] [2]. It is widely accepted that interventions to slow down or halt the disease should be administered at the earliest possible stage, before neuronal damage has occurred. "
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    ABSTRACT: The need for effective treatments halting Alzheimer's disease (AD) urges the discovery of the earliest possible biomarkers. Agrin is increased in the early stages of AD and is involved in amyloid-β (Aβ) fibrillation and synaptogenesis. We investigated the potential of agrin as an early AD cerebrospinal fluid (CSF) biomarker. We analyzed the agrin CSF concentration in nondemented controls (n = 20) and those with mild (n = 20) and severe (n = 20) AD. The levels of agrin CSF were not significantly divergent among the different patient groups and did not correlate with the concentration of Aβ42, total tau, phosphorylated tau, or the Mini Mental State Examination scores. However, agrin strongly correlated with age in those with dementia. The results indicate that agrin cannot be used as an early AD CSF biomarker using the current immunoassay. However, our population was relatively young; thus, the correlation between agrin and age suggests that stronger differences in agrin concentrations might be found in older groups with more heterogeneous AD pathologic features.
    03/2015; 1(1):75-80. DOI:10.1016/j.dadm.2014.11.008
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