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Disruption in the activity of synapses and the loss of synapses are regarded as early events in the pathogenesis of Alzheimer’s disease that precede the buildup of Aβ deposits in the brain or the clinical expression of the disease. Synaptic loss is evident by the reduction of synaptic proteins in early Alzheimer’s disease and frank atrophy. The extent of synaptic decline in brains at postmortem has been shown to be associated with cognitive function in persons with early Alzheimer’s disease or mild cognitive impairment. The overstimulation of extra-synaptic N-methyl-D-aspartate (NMDA) receptors and the associated synaptic redox stress cause an influx of extracellular calcium, which initiates a series of downstream pathways involving Cdk5/dynamin-related protein 1 (Drp1), caspases, and p-tau. This culminates in mitochondrial dysfunction, apoptosis, and synaptic loss and dysfunction.
- Alzheimer’s disease
- biomarkers
- amyloid
- cerebrospinal fluid
1. Cerebrospinal Fluid Neurogranin
Neurogranin is a postsynaptic neuronal protein comprising of 78 amino acids that regulate the concentration of calmodulin and, thus, the intracellular calcium–calmodulin signaling pathway. It is mainly expressed in dendritic spines and has a role in the signaling pathway of protein kinase C, where phosphorylation of the latter lowers its ability to bind calmodulin [258,259]. Neurogranin in CSF has been suggested as a biomarker of early synaptic loss and degeneration in Alzheimer’s disease and may be a useful predictor of disease progression [260]. Its involvement in pathophysiological pathways related to Alzheimer’s disease proposes that it may be valuable when combined with other established biomarkers for the diagnosis of early disease [261].
Tarawneh et al. examined the diagnostic efficacy of neurogranin levels in a cross-sectional and longitudinal observational study of 207 cognitively normal controls and 95 individuals with early symptomatic Alzheimer’s disease [262]. The CSF neurogranin levels were significantly higher in patients with early symptomatic Alzheimer’s disease, and this differentiated them from controls, with diagnostic utility (0.71; 95% CI: 0.64–0.77) that was similar to other established cerebrospinal biomarkers [262] (Table 3). Similarly, in a longitudinal study of 37 cognitively normal individuals and 65 patients with Alzheimer’s disease within the memory-clinic-based Amsterdam Dementia Cohort, baseline CSF neurogranin levels in patients with the disease were significantly higher than in cognitively normal participants [263]. It is interesting to note that baseline CSF neurogranin levels were highly associated with p-tau-181 and t-tau but not with Aβ42 [263]. In another study published in the same year, CSF neurogranin levels were elevated in patients with Alzheimer’s disease and positively related with CSF t-tau protein and negatively with Aβ42/Aβ40 [264]. A recent meta-analysis demonstrated that CSF neurogranin levels were significantly greater in Alzheimer’s disease patients compared with individuals with normal cognitive function [265]. High levels of CSF neurogranin in neurologically healthy older adults have been found to be associated with older age and lower levels of CSF t-tau and p-tau proteins but not with Aβ42 [266].
Table 3. Pathological mechanisms (synaptic dysfunction, neuronal injury) and associated biomarkers of Alzheimer’s disease and the findings of related studies.
| Pathological Mechanism | Biomarker | Study Design Cohort-Participants | Main Findings | References |
|---|---|---|---|---|
| Synaptic dysfunction | Neurogranin | A cross-sectional and longitudinal observational study of 95 AD patients and 207 controls | CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (0.71, 95% CI, 0.64–0.77) | [262] |
| Synaptic dysfunction | Neurogranin | Retrospective cohort of 331 participants, including 19 controls, 100 AD, 20 FTD, 13 LBD, 21 PD | Median CSF neurogranin levels higher in AD compared to all other disease groups (all p < 0.001); t-tau (p < 0.001) and p-tau (p < 0.001) | [267] |
| Synaptic dysfunction | SNAP-25 | Three separate cohorts of patients | Significantly higher levels of CSF SNAP-25 fragments in Alzheimer’s disease, even in the very early stages; differentiated Alzheimer’s disease from controls with AUC of 0.901 (p < 0.0001) | [268] |
| Synaptic dysfunction | SNAP-25 | 139 participants from the ADNI database with normal (CN, n = 52), stable mild cognitive impairment (sMCI; n = 22), progressive MCI (pMCI; n = 47), and dementia due to AD (n = 18) | CSF SNAP-25 and SNAP-25/Aβ42 were increased in patients with pMCI and AD compared with CN, and in pMCI and AD compared with sMC; significantly predicted conversion from MCI to AD | [269] |
| Synaptic dysfunction | GAP-43 | 43 healthy controls, 275 AD, and 344 patients with other neurodegenerative diseases | GAP-43 was significantly increased in AD compared to controls and most neurodegenerative diseases; correlated with the magnitude of t-tau and Aβ plaques | [270] |
| Synaptic dysfunction | GAP-43 | 47 AD patients, 17 FTD, 16 VaD, and 12 age-matched controls | GAP-43 increased in AD compared to FTD (p < 0.01); positive and highly significant correlation with t-tau | [271] |
| Neuronal injury | VILP-1 | 33 AD patients and 24 controls; VLP-1 levels measured using ELISA | VILP-1 concentrations were significantly higher in AD patients (365 ± 166 ng/L) compared to controls (244 ± 142.5); correlation with p-tau (r = 0.809) | [272] |
| Neuronal injury | VILIP-1 | 61 AD patients, 32 DLB patients, and 40 normal controls using commercial ELISA kits to measure VILIP-1 | VILIP-1 level had significantly increased in AD patients compared with controls and DLB patients and accurately diagnosed AD; positively t-tau and p-tau-181P | [273] |
| Neuronal injury | Neurofilament light | CSF neurofilament (NfL) levels were measured in 221 participants from the Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing (AIBL). | NfL levels, as well as NfL/Aβ42, were significantly elevated in AD compared to healthy controls (HC, p < 0.001); NfL and NfL/Aβ42 differentiated AD from HC, with AUC of 0.84 and 0.90, respectively | [274] |
| α-synuclein pathology | α-Synuclein | Cohort of 225 AD patients and 68 cognitively intact controls | CSF total α-syn significantly increased in the AD group (p < 0.0001) compared to controls; sensitivity 85% and specificity of 84% (AUC = 0.88) in distinguishing AD from controls | [275] |
| α-synuclein pathology | α-Synuclein | Cohort of approximately 400 healthy control, MCI, and AD subjects in the Alzheimer’s Disease Neuroimaging Initiative | CSF α-synuclein levels were significantly higher in the MCI (p = 0.005) and AD (p < 0.001) groups compared to controls; AUC of sensitivity (65%) and specificity (74%) as a diagnostic marker of AD | [276] |
| Iron toxicity | Ferritin | PD, AD, and multiple system atrophy (MSA) as well as control subjects | Significant increase in CSF ferritin in AD compared with both PD and age-matched controls | [277] |
| Iron toxicity | Ferritin | Longitudinal study involving 296 patients (followed for up to 5 years) | Elevated CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ42 | [278] |
| Neurodegeneration and neuroinflammation | miRNAs | Profile of miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays | 36 miRNAs that discriminate AD from control; linear combinations of 3 and 4 miRNAs have AUC of 0.80–0.82 | [279] |
| Neurodegeneration and neuroinflammation | miRNAs | 10 AD patients and 10 patients diagnosed with either vascular dementia, frontotemporal dementia, or dementia with Lewy bodies | Fifty-two miRNAs were detected in CSF in at least nine out of ten patients in both groups; let-7i-5p and miR-15a-5p were significantly upregulated and miR-29c-3p significantly downregulated in AD patients | [280] |
Alzheimer’s disease (AD); Lewy bodies (DLB); frontotemporal lobar degeneration (FTLD); vascular dementia (VaD); Parkinson’s disease with dementia (PDD); Parkinson’s disease (PD); Parkinson’s disease with dementia (PDD); mild cognitive impairment (MCI); enzyme-linked immunosorbent assay (ELISA).
Studies have shown elevated levels of CSF neurogranin in patients with mild cognitive impairments and in the predementia stage of Alzheimer’s disease [281,282]. In the ADNI cohort study, CSF neurogranin levels were significantly increased in Alzheimer’s disease patients with dementia and patients with stable mild cognitive impairment and progressive cognitive impairment compared with controls [281]. In another study, CSF neurogranin levels were significantly higher in patients with prodromal Alzheimer’s disease compared to individuals with mild cognitive impairment. The concentration of this biomarker was positively correlated with established axonal biomarkers of injury, such as CSF t-tau and p-tau proteins, whereas there was no correlation to CSF Aβ42 [282]. The meta-analysis by Mavroudis et al. found significantly higher levels of CSF neurogranin levels in mild cognitive-impaired patients who developed Alzheimer’s disease compared with stable mild cognitive-impaired patients [265]. However, in a study reported nine years earlier, there were no substantial differences in CSF biomarkers such as neurogranin, t-tau, and p-tau between healthy controls with normal cognitive function and patients with Alzheimer’s disease [260].
The levels of CSF neurogranin is elevated in Alzheimer’s disease dementia and may be specific for the disease [283]. In a prospective study involving 915 patients, CSF neurogranin levels were significantly and specifically elevated in Alzheimer’s disease compared with eight other neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, and frontotemporal dementia [284]. In an earlier retrospective cohort study comprised of 19 healthy controls with normal cognitive function and 331 individuals with various neurodegenerative diseases, the median CSF neurogranin level was greater in Alzheimer’s disease patients compared with the other disease groups and controls [267] (Table 3). Notably, the CSF neurogranin level was strongly correlated with p-tau and t-tau proteins [267]. In a cross-sectional multicenter study, CSF neurogranin levels were significantly greater in Alzheimer’s disease patients compared with subjects with frontotemporal dementia and healthy controls with normal cognitive function [283]. Furthermore, neurogranin and other synaptic biomarkers such as Rab3 and SNAP25 were found to predict cognitive decline in patients with Alzheimer’s disease and dementia of Lewy bodies. [285].
A number of studies have shown that CSF neurogranin levels can predict the progression of Alzheimer’s disease [262,263]. In the memory-clinic-based Amsterdam Dementia Cohort study, baseline CSF neurogranin levels were greater in patients with mild cognitive impairment who progressed to Alzheimer’s disease and were prognostic of progress from mild cognitive impairment to Alzheimer’s disease [263]. Elevated levels of CSF neurogranin at the mild cognitive impairment stage predicted progression to Alzheimer’s disease dementia (HR: 12.8, 95% CI: 1.6–103.0) [286]. Similarly, elevated baseline CSF neurogranin levels in patients with mild cognitive impairment forecasted a decline in cognition and corroborated significant longitudinal reductions of hippocampal volume at clinical follow-up [281]. Furthermore, CSF neurogranin levels projected future cognitive impairment (adjusted HR: 1.89; 95% CI: 1.29–2.78) in controls with normal cognitive function and predicted a decline in cognition in patients with symptomatic Alzheimer’s disease [262].
Overall, the data show that CSF neurogranin levels are elevated at the initial clinical stage of Alzheimer’s disease and are specific to the disease. It complements established biomarkers such as t-tau and p-tau proteins and may be a valuable addition to the existing panel of Alzheimer’s disease biomarkers. However, further validation in larger clinical studies is needed.
2. Cerebrospinal Fluid of Synaptosome-Associated Protein 25 (SNAP-25)
Synaptosome-associated protein 25 (SNAP-25) and synaptotagmin are small tail-anchored and transmembrane proteins that mediate the fusion and exocytosis of synaptic vesicles in neurons with the release of neurotransmitters [287]. During membrane fusion and exocytosis, target-cell-associated t-SNARESs and vesicle-associated v-SNAREs assemble to form a core trans-SNARE complex [288]. The core trans-SNARE complex is an established four-helix structure that connects plasma and vesicle membranes and comprises SNAP-25, which participates with two helices and syntaxin and synaptobrevin, each donating one helix [289].
SNAP-25 is encoded by the SNAP gene and is a 25 kDa presynaptic membrane-bound protein found in plasma. It plays a key role in mediating the specificity of fusion and, as part of the SNARE complex, affects the fusion of synaptic vesicles and plasma membranes [290]. This leads to exocytosis and the regulated related release of neurotransmitters, a major stage in neurotransmission that is essential to normal brain function [291]. Syntaxins are multidomain t-SNARE transmembrane proteins with a single aminoterminal cytoplasmic region (consisting of a regulatory domain and a SNARE domain) and a distinct transmembrane domain [292]. There are about 15 types of syntaxins; the 4 expressed in the plasma membrane are involved in the different stages of membrane fusion and calcium-triggered exocytosis [293].
Synaptobrevin is also known as a vesicle-associated membrane protein that has a molecular weight of 19 kDa. It is attached to the synaptic vesicle via a distinct transmembrane domain. As part of the core trans-SNARE complex, it is intricately linked to calcium-dependent exocytotic membrane fusion by the release of neurotransmitters [294]. Synaptotagmin membrane-trafficking calcium-sensing proteins are described by a distinct transmembrane domain at the N-terminus, an adapter linker domain, and two calcium-binding C2 domains, C2A and C2B [295]. There are 17 different synaptotagmin isoforms, which include calcium-binding synaptotagmins 1, 2, 3, 5, 6, 7, 9, and 10. However, in neurons, synaptotagmins 1 and 2 are the main calcium-sensing proteins that promote anionic membrane-binding with a subsequent fusion of the synaptic vesicle with the presynaptic membrane via the SNARE complex [296].
Alzheimer’s disease is described by a progressive decrease in cognition, and the pathology of the synapse is important to the clinical presentation of the disease [297]. Studies have assessed the levels of synaptic proteins such as SNAP-25, β, syntaxin, and synaptotagmin in the brains of Alzheimer’s disease patients and in controls. Postmortem investigations on the brains of Alzheimer’s disease patients have revealed different levels of these synaptic proteins, indicating that they are affected by the disease process [298,299,300].
In a study by Sze at al. (2000), synaptobrevins were decreased by 29% in the hippocampus of patients with early Alzheimer’s disease compared to controls. There were also significant reductions in synaptobrevins (46%) in the hippocampus and synaptobrevins (31%) in the entorhinal cortex of Alzheimer’s disease patients compared to controls [301]. There were decreases in synaptophysin and synaptobrevin levels by approximately 30% and 10% in levels of SNAP-25 and synaptotagmin in the brain of Alzheimer’s disease patients compared with controls [302]. In another study, mean values of SNAP-25, syntaxin, and synaptophysin levels were significantly reduced by 21–28% in the prefrontal cortex of Alzheimer’s disease patients compared with controls [303]. Likewise, there were decreased SNAP-5 levels in five brain regions of patients with Alzheimer’s disease [304] and a 25% reduction of synaptophysin levels in the frontal cortex of patients with early Alzheimer’s disease compared with controls [305]. Notably, in the latter study, the level of synaptotagmin was not different between patients with Alzheimer’s disease and controls [305]. In two recent studies worth noting, there were significantly higher levels of SNAP-25 and synaptotagmin-1 in patients with atypical Alzheimer’s disease compared to those with frontotemporal dementia [306], and patients with vascular dementia had lower CSF synaptophysin levels than their counterparts in the Alzheimer’s disease group [307].
Alzheimer’s disease is associated with cognitive impairment, and synaptic degeneration is suggested to be an early event in the pathophysiology of the disease [308]. There are studies that have investigated synaptic biomarkers in CSF and serum as potential tools for early diagnosis and monitoring disease progression [309]. In a recent study by Agliardi et al., it was noted that SNAP-25 in serum is transported by neuron-derived exosomes and its concentration was reduced in patients with Alzheimer’s disease compared with healthy controls. The sensitivity of serum SNAP-25 to discriminate between the two groups was 87.5%, with a specificity of 70.6%, and there was a significant correlation with cognitive decline in Alzheimer’s disease patients [310]. In another study, there were significantly higher levels of serum SNAP-25 in patients with atypical Alzheimer’s disease compared with controls [306]. Moreover, CSF SNAP-25 levels, determined using mass spectrometry, were significantly elevated in early-stage and established Alzheimer’s disease, and the biomarker was able to meaningfully discriminate patients with the disease from healthy controls with an area under the curve of 0.901 [311]. Notably, in a recent study, CSF SNAP-25 levels were significantly elevated in persons carrying autosomal-dominant Alzheimer’s disease mutations. It was observed that the levels of CSF SNAP were altered about 15–19 years prior to the onset of symptoms, indicating that synaptic damage commences just after the accumulation of brain amyloid-β protein [268].
The degeneration of synaptic proteins is a principal event in the development of Alzheimer’s disease that takes place early during the progression of the disease and is associated with cognitive symptoms [297]. In a recent study, CSF SNAP-25 and SNAP-25/Aβ42 were higher in patients with progressive mild cognitive impairment and those with dementia due to Alzheimer’s disease compared to normal controls. It was also observed that increased SNAP-25/Aβ42 ratios were higher in cognitively normal individuals who had progressed to mild cognitive impairment or Alzheimer’s disease patients during a follow-up [312]. Furthermore, in a study of the ADNI cohort, comprising cognitively normal, mild cognitive impairment, and Alzheimer’s disease patients who were further defined by amyloid-β status, reference point CSF SNAP-25 levels were higher in Alzheimer’s disease patients and those with mild cognitive impairment who were amyloid-β-positive than cognitively normal individuals (amyloid-β-positive or -negative [190]. Noticeably, CSF SNAP-25 levels reduced longitudinally in the group of Alzheimer’s disease patients followed for 4 years [190].
3. Cerebrospinal Fluid Synaptotagmin
Synaptotagmin is a calcium sensor presynaptic protein that is critical for the preservation of an intact synaptic transmission and cognitive function, and studies have examined whether selective or regional alterations occur in Alzheimer’s disease [269,313]. Sze et al. reported that synaptotagmin in postmortem brain tissue was significantly reduced by 38% in the hippocampus in early Alzheimer’s disease and 52% in the entorhinal cortex of definite Alzheimer’s disease compared to controls. It was observed that reduced levels of synaptotagmin were correlated with low Mini-Mental State Examination scores [301,302]. In a recent study, synaptotagmin 2 was significantly reduced in postmortem brain tissue of Alzheimer’s disease patients and reliably discriminated Alzheimer’s disease from Parkinson’s disease dementia [314]. Other studies have found similar observations in postmortem brain tissue, such as a 35% reduction in the cortex of patients with severe Alzheimer’s disease [269] and progressive decrement in patients with early Alzheimer’s disease with clinical dementia ratings of >1 [315].
Ohrfelt et al. assessed CSF synaptotagmin-1 levels and found a significant elevation in patients with both mild cognitive impairment and dementia due to Alzheimer’s disease. It was also observed that CSF synaptotagmin-1 levels in patients with dementia due to Alzheimer’s disease were significantly lower compared to those with mild cognitive impairment due to Alzheimer’s disease [316]. Interestingly, in a recent study, CSF synaptotagmin-1 levels were higher in Alzheimer’s disease patients compared to those with frontotemporal dementia, and there was a tendency to increased levels in patients with likely tau pathology [306].
In summary, studies have shown that synaptotagmin is reduced in the postmortem brain tissue of Alzheimer’s disease patients and may show a relationship with cognitive decline. CSF synaptotagmin is likely to be a promising biomarker as it is elevated in early-onset Alzheimer’s disease and there is an association with tau pathology.
4. Cerebrospinal Fluid Growth-Associated Protein 43 (GAP-43)
Growth-associated protein 43 (GAP-43), also identified as neuromodulin, is a 43 kDa neuron-specific presynaptic phosphoprotein found at high levels in neuronal growth cones and axon terminals in the adult human brain [317]. It is chiefly expressed in regions of the developed central nervous system that display high plasticity, such as olfactory bulbs, neocortex, entorhinal cortex, cerebellum, and hippocampus [318]. GAP-43 is involved in the regulation of the growth and development of neurons via the activity of protein kinase C, synaptogenesis, and nerve terminal plasticity, as well as memory and learning [319].
There are studies that have investigated the quantity and distribution of GAP-43 in postmortem brain tissue. Davidsson and Blennow reported a reduction of GAP-43 in the frontal cortex of early-onset and late-onset Alzheimer’s disease patients [255]. In a later study by the same authors, there was significantly decreased GAP-43 expression in the hippocampus (81% of control value) and frontal cortex (70% of control value), a positive correlation with duration of dementia, and a negative relationship with the number of senile plaques in the hippocampus [320]. Remarkably, in the investigation of neuroplasticity activity in the brain of Alzheimer’s disease, Rekart et al. found subfield-specific elevation of GAP-43 expression in the hippocampus and stratum lacunosum that was associated with the severity of the disease [321].
The level of CSF GAP-43 has been demonstrated to be elevated in Alzheimer’s disease and may be valuable in early disease detection [322,323,324]. Sandelius et al. recently reported significantly elevated levels of GAP-43 in Alzheimer’s disease compared to healthy controls, with patients with normal cognition and other neurodegenerative diseases. Higher GAP-43 levels were associated with the amount of Aβ plaques and neurofibrillary tangles but not with TDP-43 expression or CSF α-synuclein levels [322] (Table 3). There are other studies that have supported such observations. In an earlier study, CSF GAP-43 was significantly elevated in Alzheimer’s disease patients compared to age-matched healthy controls and patients with frontotemporal dementia. There was a highly significant association between GAP-43, CSF t-tau, and CSF soluble amyloid precursor protein in patients with neurodegenerative disorders, including vascular dementia [323] (Table 3). Likewise, in an explorative study involving 441 human samples of lumbar CSF taken antemortem and ventricular samples collected postmortem, CSF GAP-43 was elevated in two cohorts of preclinical and clinical Alzheimer’s disease matched to healthy controls. It was noted that there were significant elevations in CSF GAP-43 in dementia with Lewy bodies and Parkinson’s disease compared to controls [324]. Finally, in a recently published retrospective study, CSF GAP-43 was significantly elevated in mild cognitive-impaired Alzheimer disease patients and Alzheimer’s disease dementia patients compared to neurological controls and displayed good discriminatory power in making the distinction between patients with the disease and those with other dementias [325].
In summary, immunohistochemistry and quantitative tests on postmortem brain tissue found reduced GAP-43 in the hippocampus and frontal cortex, which was associated with senile plaques and duration of dementia. CSF GAP-43 levels are increased in Alzheimer’s disease patients compared with other neurodegenerative disorders such as Parkinson’s disease and frontotemporal dementia and may be useful in the differential diagnosis of the disease. Thus, the determination of CSF GAP-43 could possibly be of great significance in prospective tests for Alzheimer’s disease.
This entry is adapted from the peer-reviewed paper 10.3390/brainsci11020215
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