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)
"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  . 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. "
[Show abstract][Hide abstract] 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.
"Structural and functional synaptic changes are observed in both early and late stages of AD (Sze et al., 2000; Masliah et al., 2001; Honer, 2003; Reddy et al., 2005; Counts et al., 2006). Moreover, these changes correlate well with the cognitive decline in AD (DeKosky and Scheff, 1990; Braak and Braak, 1991; Arriagada et al., 1992; Blennow et al., 1996; Callahan et al., 2002). The synaptic damage is characterized by deregulation of synaptic proteins at the protein and mRNA levels (Coleman and Yao, 2003; Honer, 2003; Tao et al., 2003). "
[Show abstract][Hide abstract] 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.
"Astroglial atrophy may be directly linked to a reduction of astroglial homeostatic support, which may have dire consequences for performance and survival of neurones as well as may affect functional activity of synapses. All of this can result in trimming synaptic contacts, affecting transmission and weakening synaptic plasticity, which are precisely the early pathological events observed in AD (Terry, 2000; Coleman et al., 2004); a decrease in synaptic densities has been reported to correlate with the severity of dementia (DeKosky and Scheff, 1990; Samuel et al., 1994). Astrocytes support synaptic transmission through multiple mechanisms (Verkhratsky and Nedergaard, in press). "
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