Sci Adv: Monosynaptic Analysis in Alzheimer's Disease

 

 The anatomical basis of cognitive impairment in Alzheimer's disease (AD) is loss of limbic and neocortical synapses
.

 The anatomical basis of cognitive impairment in Alzheimer's disease (AD) is loss of limbic and neocortical synapses
.

 

SynTOF (time-of-flight synaptometry) quantifies tens of millions of individual synaptic events by mass spectrometry, analyzed by machine learning ( ML) .
Here, we performed SynTOF in non-human primates (NHPs) , PS/APP mice, and individuals with only AD neuropathic changes (ADNC) or only Lewy body disease (LBD) .

SynTOF (time-of-flight synaptometry) quantifies tens of millions of individual synaptic events by mass spectrometry, analyzed by machine learning ( ML) .

Here, we performed SynTOF in non-human primates (NHPs) , PS/APP mice, and individuals with only AD neuropathic changes (ADNC) or only Lewy body disease (LBD) .

 

Recently, Professor Montine's team from Stanford University believes that the single synapse analysis of AD with SynTOF has verified the pathological proteins of previous studies and discovered new protein changes (DJ1, CD47)
.

Recently, Professor Montine's team from Stanford University believes that the single synapse analysis of AD with SynTOF has verified the pathological proteins of previous studies and discovered new protein changes (DJ1, CD47)
.

Monosynaptic analysis of AD with SynTOF verified the pathological proteins of previous studies, and found new protein changes (DJ1, CD47) .
Monosynaptic analysis of AD with SynTOF verified the pathological proteins of previous studies, And found new protein changes (DJ1, CD47)

 

 

 

Extensive analysis of human and mouse monosynaptic events

Extensive analysis of human and mouse monosynaptic events Extensive analysis of human and mouse monosynaptic events Extensive analysis of human and mouse monosynaptic events

 

17 million single synaptic events were analyzed
.

The first goal is to analyze the data by the established method and compare it

17 million single synaptic events were analyzed

When ADNC was compared to the control group, the mean percentage of presynaptic positive events was significantly different for the two antibody probes, with more PHF-tau in the hippocampus and less DJ1 in BA9 (Fig.

1C)

When ADNC was compared to the control group, the mean percentage of presynaptic positive events was significantly different for the two antibody probes, with more PHF-tau in the hippocampus and less DJ1 in BA9 (Fig.

The mean percentage of presynaptic positive events for the 11 antibodies was significantly increased in PS/APP compared to WT mice
.

Presynaptic Aβ accumulation in aged PS/APP mice was increased by approximately 100-fold by SynTOF, as well as many responses to Aβ-induced injury

The mean percentage of presynaptic positive events for the 11 antibodies was significantly increased in PS/APP compared to WT mice

 Figure 1: SynTOF results in human and mouse synaptosomes

 Figure 1: SynTOF results in human and mouse synaptosomes

 

 

Identifying subpopulations from human presynaptic events

Identifying subpopulations from human presynaptic events Identifying subpopulations from human presynaptic events

 

We employ AE to learn compressed hidden representations of monosynaptic data and perform clustering
.

Figure 2A shows the normalized mean expression of each antibody for each subpopulation in all brain regions versus control samples

We employ AE to learn compressed hidden representations of monosynaptic data and perform clustering

The 11 subgroups of subgroup C were heterogeneous; antibody signals from C1 to C5 tended to be higher than those from C6 to C11
.

The markers were highest in subgroup A and lowest in subgroup B (Fig.
2A)
.
The presynaptic markers CD47 and SNAP25 showed similar moderate to high expression in all subgroups except subgroup B (Fig.
2C)
.
There were significant differences in the frequency of subpopulations in different brain regions
.
In most subgroups, BA9 is similar to the caudate gland, while the hippocampus tends to be different from the other two regions
.

The 11 subgroups of subgroup C were heterogeneous; antibody signals from C1 to C5 tended to be higher than those from C6 to C11
.
The markers were highest in subgroup A and lowest in subgroup B (Fig.
2A)
.
The presynaptic markers CD47 and SNAP25 showed similar moderate to high expression in all subgroups except subgroup B (Fig.
2C)
.
There were significant differences in the frequency of subpopulations in different brain regions
.
In most subgroups, BA9 is similar to the caudate gland, while the hippocampus tends to be different from the other two regions
.
In most subgroups, BA9 is similar to the caudate gland, while the hippocampus tends to be different from the other two regions
.
In most subgroups, BA9 is similar to the caudate gland, while the hippocampus tends to be different from the other two regions
.

 

Figure 2: Modified deep AE clusters control sample presynaptic events into distinct phenotypic marker-based subpopulations

Figure 2: Modified deep AE clusters control sample presynaptic events into distinct phenotypic marker-based subpopulations

 

We next focused on using conventional ML to identify regional differences in presynaptic molecular composition in control, ADNC, and LBD groups
.
The EN model outperforms other algorithms
.
Correction showed that an increase in the mean intensity of PHF-tau in the hippocampus and a decrease in the mean intensity of BA9 DJ1 clearly separated ADNC from controls (Fig.
3C) ; both signals were evident in each subpopulation (Fig.
3D)
.

We next focused on using conventional ML to identify regional differences in presynaptic molecular composition in control, ADNC, and LBD groups
.
The EN model outperforms other algorithms
.
Correction showed that an increase in the mean intensity of PHF-tau in the hippocampus and a decrease in the mean intensity of BA9 DJ1 clearly separated ADNC from controls (Fig.
3C) ; both signals were evident in each subpopulation (Fig.
3D)
.

 

Another strong feature was the increased average expression of CD47 in the hippocampus of ADNCs (Fig.
3C) , especially in the CD47-high subpopulation (Fig.
3E) , which also tended to express higher PHF-tau
.
Unlike CD47 (Fig.
3E) , another presynaptic marker, SNAP25 (Fig.
3F and Fig.
S7), did not have a strong signal
.

Another strong feature was the increased mean expression of CD47 in the hippocampus of ADNCs (Fig.
3C) , especially in the subpopulation with high CD47 (Fig.
3E) , they Also tends to express higher PHF-tau
.
Unlike CD47 (Fig.
3E) , another presynaptic marker, SNAP25 (Fig.
3F and Fig.
S7), did not have a strong signal
.

 

Figure 3: Modeling and univariate analysis of subpopulations identified unique signals for ADNC

Figure 3: Modeling and univariate analysis of subpopulations identified unique signals for ADNC

 

Presynaptic features suggest AD dementia

Presynaptic features suggest AD dementia

Molecular differences between and AD recovery cases

Molecular differences between and AD recovery cases

 

Resilience describes the ability to maintain cognitive function despite high levels of pathological changes
.
Of the nine ADNCs analyzed, there were two AD elastic cases whose Q-scores were recalculated
.

Resilience describes the ability to maintain cognitive function despite high levels of pathological changes
.
Of the nine ADNCs analyzed, there were two AD elastic cases whose Q-scores were recalculated
.

 

This analysis resulted in an increase in the intensities of existing signals, especially DJ1 in more subpopulations in BA9 (Fig.
4A) , except for PHF-tau and CD47, which remained unchanged
.
Several new signals also emerged, the strongest of which were apolipoproteins from hippocampal A1 and C5 subpopulations (Fig.
4B)
.

This analysis resulted in an increase in the intensities of existing signals, especially DJ1 in more subpopulations in BA9 (Fig.
4A) , except for PHF-tau and CD47, which remained unchanged
.
Several new signals also emerged, the strongest of which were apolipoproteins from hippocampal A1 and C5 subgroups Apolipoproteins from hippocampal A1 and C5 subgroups (Fig.
4B)
.

 

Figure 4 : Important features and changes in signal intensity in AD dementia cases

Figure 4 : Important features and changes in signal intensity in AD dementia cases

 

 

MIBI-TOF of tissue sections

MIBI-TOF of tissue sections

Analysis supports SynTOF findings

Analysis supports SynTOF findings

 

MIBI by TOF (MIBI-TOF) was used to support the physical presence of subpopulations identified by AEs
.
Scanning control group and ADNC hippocampal CA1 region composition Figure 5A
.
Figure 5B shows examples of the staining of synapsin, CD47 and PHF-tau with different ratios of FOVs
.
MIBI-TOF confirmed the three main findings of SynTOF
.

MIBI by TOF (MIBI-TOF) was used to support the physical presence of subpopulations identified by AEs
.
Scanning control group and ADNC hippocampal CA1 region composition Figure 5A
.
Figure 5B shows examples of the staining of synapsin, CD47 and PHF-tau with different ratios of FOVs
.
MIBI-TOF confirmed the three main findings of SynTOF
.

 

First, MIBI-TOF showed a high degree of colocalization of multiple positive markers; second, the presynaptic homotopy of CD47 and PHF-tau observed in SynTOF was also observed by MIBI
.
Finally, the mean expression levels of both PHF-tau and CD47 were higher in the ADNC presynaptic window than in the control group
.

First, MIBI-TOF showed a high degree of colocalization of multiple positive markers; second, the presynaptic homotopy of CD47 and PHF-tau observed in SynTOF was also observed by MIBI
.
Finally, the mean expression levels of both PHF-tau and CD47 were higher in the ADNC presynaptic window than in the control group
.

 

Figure 5: Analysis of MIBI-TOF images supports SynTOF findings

Figure 5: Analysis of MIBI-TOF images supports SynTOF findings

 

 

Summarize

Summarize

 

Time-of-flight synaptometry (SynTOF) measures monosynaptic events across species
.
Clustering and pattern recognition of human synapses revealed expected disease-specific differences such as increased hippocampal pathological tau in AD and decreased caudate dopamine transporter in LBD, and found increased hippocampal CD47 and decreased DJ1 in AD , and high apolipoproteins in dementia in AD
.
These results suggest a greater understanding of neurodegenerative diseases through SynTOF
.

Time-of- flight synaptometry Time -of-flight synaptometry (SynTOF) measures monosynaptic events across species
.
Clustering and pattern recognition of human synapses revealed expected disease-specific differences such as increased hippocampal pathological tau in AD and decreased caudate dopamine transporter in LBD, and found increased hippocampal CD47 and decreased DJ1 in AD , and high apolipoproteins in dementia in AD
.
These results suggest a greater understanding of neurodegenerative diseases through SynTOF
.
Gain a deeper understanding of neurodegenerative diseases with SynTOF
.
Gain a deeper understanding of neurodegenerative diseases with SynTOF
.

 

 

References References

Phongpreecha T, Gajera CR, Liu CC, et al.
Single-synapse analyses of Alzheimer's disease implicate pathologic tau, DJ1, CD47, and ApoE.
Sci Adv.
2021;7(51):eabk0473.
doi:10.
1126/sciadv.
abk0473

Phongpreecha T, Gajera CR, Liu CC, et al.
Single-synapse analyses of Alzheimer's disease implicate pathologic tau, DJ1, CD47, and ApoE.
Sci Adv.
2021;7(51):eabk0473.
doi:10.
1126/sciadv.
abk0473

 

Compiler: Meow ( brainnews creative team )

Compilation Author: Meow ( brainnews Creation Team )
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Reviewer : Simon ( brainnewseditorial board)

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