Written by - Chen Chang Responsible Editor - Wang Sizhen Editor - Yang Binwei

Alzheimer's disease (AD), a degenerative disease of the central nervous system with progressive cognitive dysfunction and behavioral abnormalities as the main clinical manifestations, is the most common type of Alzheimer's disease, and there is currently no effective treatment strategy [1-3
].

The brain pathology of AD is characterized by age spots formed by abnormal aggregation of β-amyloid (Aβ), neurofibrillary tangles (NFTs) formed by abnormal phosphorylation of tau proteins, and loss
of neurons.

These molecular mutants can cause severe brain network damage, synaptic loss, inflammation, and progressive cognitive decline [4,5
].

Compared with late-onset AD, early-onset familial AD can be caused by a single genetic mutation, usually the amyloid precursor protein (APP) or progerin (PSEN1, PSEN2) gene
.

From brain development in early embryos to senescence, mutant genes and products are expressed throughout the life cycle [6,7].


There is much research on how these mutant proteins affect aging and degraded brains, and little is known about their effects during early brain development
.

In September 2022, the team of Bai Feng of Drum Tower Hospital Affiliated to Nanjing University School of Medicine and Shenfeng Qiu of the University of Arizona School of Medicine published an online presentation on Translational Psychiatry titled "Early impairment of cortical circuit plasticity and connectivity in the 5XFAD Alzheimer's.

Both PFC and layer 5 (L5) neurons in the VC region of 5xFAD exhibit increased age-dependent APP immune staining intensity, and early overexpression of APP mutant forms can impair synaptic function and plasticity
.

Studies have shown that the hippocampal CA1 region of 5xFAD mice exhibits impairment of LTP at 4–6 months of age [8].


It has also been reported that the LTP of CA1 weakens as early as 10 weeks of age [9].


In adult mice, LTP disturbances due to differences in Aβ pathology in specific cortical regions have been reported[10].


Considering the selective high expression of early APP in L5 neurons, the authors first performed field potential recording and LTP (recording electrode placed at L5 and stimulation electrode at L2/3) in PFC slices of early weaned (P22-30) mice, but did not observe differences between
5xFAD mice and Ctrl mice.

Therefore, the authors infer that sustained high APP load may impair LTP
in the PFC region L5 at a later age.

The results (Figure 1) show that LTP decreases sharply at P42-56 in 5xFAD mice, which is the period when the
APP load rises significantly.

Figure 1.
5xFAD mice have impaired prefrontal LTP at 6-8 weeks of age (Source: Chen C et al.
, Transl Psychiatry, 2022)
Next, the authors investigated how the overexpression of the mutant APP/PS1 affects neuronal membrane properties and intrinsic excitability
by aggregating in L5 pyramidal neurons in the visual cortex.

The authors first performed a whole-cell patch-clamp recording of the visual cortex coronary brain sections of P28-32 5xFAD and WT mice, and tested the membrane properties of L5 neurons, and the results (Figure 2) found that 5xFAD and WT mouse neurons had no difference in input resistance and membrane capacitance, and that the neurons of the two groups of mice showed similar action potential half-width and action potential thresholds
.

It was shown that there was no difference in the modeling of L5 neurons in
the visual cortex of the two groups of mice.

So the authors went on to test the intrinsic excitability of
neurons.

The -100pA-500pA is input into the neuron at a 50pA increasing current, and the analysis of the results (Figure 2) shows that the 5XFAD neuron shows a weakened action potential response to the current input current, and the action potential trigger frequency is significantly reduced
under the 300-500pA current stimulation.

The results show that due to the expression of APP/PS1 mutants, the L5 neurons of the visual cortex in developing 5xFAD mice show a decrease
in intrinsic excitability.
Figure 2.
The intrinsic excitability of neurons in the visual cortex layer 5 at P28-32 in 5XFAD mice was reduced (Source: Chen C et al.
, Transl Psychiatry, 2022)
The authors then explored the effect of the expression of transgenic mutation APP/PS1 on the synaptic activity of L5 neurons at the critical stage of
visual cortex development (P28-32).

The authors first recorded a tiny excitatory postsynaptic current (mEPSC), and the results (Figure 3) found that the mean amplitude of mEPSC in 5XFAD neurons decreased, while there was no significant difference in
mEPSC frequency.

Tiny inhibitory postsynaptic currents (mIPSC) were then recorded, and the results (Figure 3) found that the mean mIPSC amplitude of 5XFAD neurons decreased, and there was also no difference in
mIPSC frequency.

These changes in mEPSC/mIPSC reflect changes in spontaneous input from presynaptic sources (from L2/3
).

The decrease in amplitude of mEPSC and mIPSC without change in frequency indicates that the postsynaptic mechanisms associated with the incubation of synapses in neurons are impaired, either as a result of developmental deficits or due to early loss
of excitatory and inhibitory synapses.
Figure 3.
5XFAD Visual Cortex Layer 5 neurons at developmental critical periods (P28-32), synaptic mEPSC and mIPSC spontaneous input decreases (Source: Chen C et al.
, Transl Psychiatry, 2022)

The authors used LSPS mapping combined with glutamate decage to study synaptic connectivity on V1-L5 pyramidal neurons in coronary brain sections
.

The L5 neurons of the visual cortex of 5XFAD mice and WT mice with the same litter, P25-35, are clamped with voltage, and at different sites near the clamping neurons, glutamic acid is released under high-energy laser stimulation, and the neurons that activate this site generate excitatory or inhibitory currents
.

Voltage clamp can record the direct response current or synaptic-mediated postsynaptic current
that clamp the neuronal cell body.

A "map"
of local loop connections is constructed from recorded excitatory or suppressive currents.

After collecting mapping data from multiple cells, we compared excitatory and inhibitory input profiles of L5 neurons in the visual cortex of 5XFAD and WT in two groups of mice, and the results (Figure 4) found that L5 neurons received the primary input
from L2/3.

The strength of quantitative connectivity showed that overall connectivity decreased in 5xFAD mice
.

In addition, the L2/3 combination input in 5XFAD neurons was significantly reduced
.

Quantification of the intensity of inhibitory input from L5 neurons in the visual cortex found that the overall inhibitory ligation pattern of 5xFAD neurons was significantly reduced
.

Inhibitory inputs from L2/3 and L5 also showed a significant reduction
.

These data suggest that during the critical period of plasticity development of the visual cortex, the excitability and inhibition of L5 neurons in the visual cortex, especially the inhibitory synaptic connections, decrease
.

Figure 4.

Based on the above findings, the authors suggest that overexpression of transgenic mutation APP/PS1 in 5XFAD mice may affect the plasticity
of the visual cortex critical phase in 5XFAD mice.

The authors used monocular deprivation (MD) in combination with monocular recordings to investigate potential changes in
the plasticity of critical periods in mice with 5XFAD.

Results (Figure 5) found that after 4 days of MD shifted the eyeball dominance index (ODI) distribution curve to the right in WT mice, and calculated the contralateral bias index (CBI) of each mouse based on a single ODI score, it was found that MD led to a significant decrease
in the CBI score in WT mice.

Compared to the ODI value of WT mice without deprivation (ND), the ODI value of WT mice after MD shifted
to the right.

The same MD protocol did not significantly alter the ODI distribution curve
of 5XFAD mice compared to WT mice.

Compared to 5XFAD mice for ND, MD had no significant effect
on CBI scores in 5XFAD mice.

These results suggest that MD-induced ocular dominance plasticity is absent in 5XFAD mice during the critical phase of visual cortex development, i.
e.
, monocular deprivation-induced ocular dominance plasticity is impaired
in 5xFAD mice.
Figure 5.
5XFAD mice visual cortex critical period plasticity impairment (Source: Chen C et al.
, Transl Psychiatry, 2022)
Conclusion and discussion, inspiration and prospect In summary, this study in the most commonly used mouse model of Alzheimer's disease 5XFAD revealed that the overexpression of the mutant form APP/PS1 destroys the development
of early cortical circuits.

This finding complements synaptic pathology studies in mice with 5XFAD, enhancing the convertibility and utility of the model to help develop interventions to prevent or slow disease progression
.

The main findings of this study were early defects in the plasticity of cortical circuits in the prefrontal cortex and visual cortex during critical periods
.

This defect was detected in in vivo 5xFAD mice (MD-induced visual cortex critical period plasticity) and ex vivo (LTP in brain sections of the prefrontal cortex), suggesting that impaired cortical circuit plasticity during development may be a dysfunction
common to all cortical regions.

However, the study has not yet investigated the mechanism of plasticity damage in the 5XFAD cortical circuit, and the mutant APP/PS1 and Aβ high loads may be the cause of plasticity damage in the prefrontal cortex and visual cortical circuits, but the study does not directly correlate
with it.

Transgenic mutation APP/PS1 overexpression has a profound effect on the development of cortical circuits, so changes in neuronal function may begin early in life and ultimately affect neuronal degeneration in later life
.

Original link: https://doi.

One of the corresponding authors: Bai Feng (Photo provided by: Bai Feng, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University)

About the Corresponding Author (Swipe Up and Down to Read)

Bai Feng is a professor and doctoral supervisor of the Department of Neurology of the Drum Tower Hospital Affiliated to Nanjing University School of Medicine, and the vice president
of Taikang Xianlin Drum Tower Hospital affiliated to Nanjing University School of Medicine.

Winner of the National Outstanding Youth Fund, New Century Excellent Talents of the Ministry of Education, Outstanding Young Neurists of China, Key Medical Talents of Jiangsu Province, etc
.

Academic part-time: Vice Chairman of the Cerebral Minor Vascular Disease Branch of the Chinese Stroke Society, Vice Chairman of the Youth Committee of the Neurology Branch of the Chinese Association for the Promotion of Medical Sciences, Vice Chairman of the Neurology Branch of the Jiangsu Geriatric Society, Chairman of the Youth Committee of the Jiangsu Stroke Society, etc
.

Research directions: neuroimaging characteristics of cognitive impairment and its molecular mechanism, published more than 90 SCI papers, presided over 5 projects of the National Natural Science Foundation of China and 7 provincial and ministerial projects, and the research results won 4 first prizes
of provincial and ministerial scientific and technological progress awards as an important component.

Selected articles from previous issues

[1] J Neurosci-Li Shao/Ma Tonghui team revealed the orthogonal array structure of AQP4 in aquaporin point mutation depolymerization mice and reduced its polar distribution at astrocyte endpodium

[2] Cereb Cortex—Yu Yuguo team-built a human brain energy and activity map to reveal the law of energy distribution

[3] Inflamm Regen—Wu Anguo/Qin Dalian/Wu Jianming's team revealed that the seedling medicine to catch the yellow herb active monomer improved the pathology of Alzheimer's disease

[4] Transl Psychiatry—Reticular meta-analysis: Drug treatment strategies for hyperprolactinemia caused by antipsychotics

[5] Nat Metab-Xiong Wei's research group elucidated a new target for alcohol and cannabis to synergistically lead to sports toxicity

[6] PloS Genet—Lingyan Xing/Liucheng Wu/Junjie Sun collaborated to reveal a new mechanism of non-cellularized degeneration of motor neurons in spinal muscular atrophy

[7] Neuron—a new molecular mechanism by which synaptic initiating proteins regulate ultrafast endocytosis

[8] JNNP-Qiu Wei/Yu Qingfen's team discovered a susceptibility gene for familial optic nerve myelitis spectrum disease

[9] Nat Neurosci - Breakthrough! Electrical stimulation of the brain can sustainably improve work and long-term memory in older adults

[10] Nat Methods—Zhang Yang's team released a common structure comparison algorithm for proteins/nucleic acids and their complexes: US-align

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References (swipe up and down to read)

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End of article