Science Translational Medicine: The "energy factory" of neurons in early Alzheimer's patients has dysfunction!

*For medical professionals only

Alzheimer's disease is the most common neurodegenerative disease, the main symptoms of which are loss of cognition and memory, as well as decreased social and physical function, usually manifested
only after the pathologic accumulation of the disease to a certain extent.

In the study of Alzheimer's disease, the most classic pathological markers are amyloid and tau deposition [1-3], which also derives the two most mainstream hypotheses about Alzheimer's disease
.

However, the drugs developed for these two proteins and hypotheses have repeatedly been broken in clinical trials
.

As a result, scientists began to rethink hypotheses and the causal relationship of diseases, and moved their attention to earlier cellular activity
.

More recent research has shifted to the cellular mechanisms
that influence the formation of two pathological proteins than earlier focused on amyloid and tau deposition itself.

Mitochondria act as "energy factories" in cells, and their dysfunction plays an important role in the pathology of many diseases, including Alzheimer's disease[4].


But in Alzheimer's disease, the relationship between mitochondrial damage and other pathological mechanisms that have been discovered is unclear
.

A recent study published in Science Translational Medicine by scholars at Imperial College and the University of Cambridge provides in vivo imaging evidence for the relationship between mitochondrial damage and endoplasmic reticulum stress and neuronal synaptic loss that are widespread in early Alzheimer's disease [5].

More and more researchers and scholars believe that the occurrence and development of Alzheimer's disease has an important relationship
with whether the metabolic function of cells in the brain is sound.

One of the characteristics of early Alzheimer's disease is that although metabolic dysfunction is widespread in various brain regions, there is regional selectivity
in its pathological markers.

This is the result of different brain regions being different to disease sensitivity, and is also determined
by the way of connectivity, functional activity and metabolic mechanism of different brain regions.

Over the years, one of the difficulties in the treatment of Alzheimer's disease is that in the early stage of the disease, because the brain has a certain plasticity and functional reserve ability, so despite some metabolic dysfunction, patients can still maintain normal cognitive levels
.

Therefore, if treatment is performed when cognitive level declines, it is possible that the optimal treatment time
has been missed.

Therefore, determining the metabolic pathological process in the early stages of Alzheimer's disease can provide new ideas and priorities for subsequent treatment
.

In the study, the researchers recruited 12 patients with early-stage sporadic Alzheimer's disease as a trial group, and 16 cognitively normal volunteers as a control group, followed them for 12-18 months
.

During the trial, radioisotope labeling of mitochondrial complex I (MC1), endoplasmic reticulum stress marker (S1R), and presynaptic vesicle protein (SV2A) in the subject's brain was studied to confirm the changes and interrelationships of
the individual markers in the disease process.

Brain imaging scans were performed by magnetic resonance imaging (MRI) to obtain changes in
the volume of the whole brain and each brain region with the test markers and disease progression.

Basic information about the patients and healthy volunteers of the subject

Changes in psychiatric cognitive ability tests after 12-18 months follow-up in patients with Alzheimer's disease

Through the lateral comparison of various brain regions and longitudinal analysis of disease individuals, the study found that compared with healthy volunteers, the brain volume of Alzheimer's disease patients showed a significant reduction, of which the hippocampus and temporal lobe were reduced by 23% and 16% (P<0.
001).

As brain volume decreases, the patient's cerebral blood flow decreases, with cerebral blood flow in each brain region reduced by between
8% and 26% compared to the healthy control group.

The largest cerebral regions with reduced cerebral blood flow are the hippocampus (-20%, P=0.
023) and the thalamus (-26%, P=0.
044).

Differences in brain volume and cerebral blood flow (CBF) in different brain regions between Alzheimer's disease patients and healthy subjects (A); and expression differences in longitudinal analysis of Alzheimer's patients (B)

The results showed that S1R was significantly elevated
in various brain regions in Alzheimer's patients.

However, in this study, the findings on elevated expression of S1R differed somewhat from
some previously published studies.

The researchers explained this because in previous studies, test subjects used drugs that blocked the binding of S1R and SA4503, and the trials differed in the selection of ligands and receptors [7-8].

The expression of the endoplasmic reticulum as an organelle in the cell is also closely related
to the number of cells.

In the middle and late stages of Alzheimer's disease, with the accumulation of disease pathology, a large number of cone cells die, so researchers also believe that the expression of S1R will increase in the early stages of the disease and then decrease
with the course of the disease.

Differences in expression of S1R, MC1 and SV2A in different brain regions between Alzheimer's disease patients and healthy subjects (A); and expression differences in longitudinal analysis of Alzheimer's patients (B)

The same as the organelles in cells, the important connection between mitochondria and endoplasmic reticulum in disease has also been valued
by scientists.

In the mitochondria there is a respiratory chain that is essential for cellular aerobic respiration, which consists of
five complexes.

MC1 is the first complex in the respiratory chain, which is related to the smooth progress of the work of the entire respiratory chain, so its expression is also an important indicator
of the completeness of mitochondrial function.

The study found that while S1R expression was up-regulated, MC1 was greatly reduced in the brains of early Alzheimer's patients, especially in disease-sensitive brain regions such as the hippocampus (-25%, P=0.
02), thalamus (-23%, P=0.
001), and caudal nucleus (-28%, P=0.
02
).

The researchers speculate that upregulation of S1R expression may be an adaptive response
to mitochondrial damage.

But the study also found that the decrease in MC1 was not correlated with the decrease in cerebral blood flow in Alzheimer's disease, meaning that in early Alzheimer's disease, mitochondrial dysfunction was not directly linked to
brain perfusion damage.

In the healthy control group, oxidative phosphorylation of mitochondria and synaptic distribution were positively correlated, while in Alzheimer's patients, this association was not found, meaning that this pathway may be dysregulated
by the occurrence of the disease.

Synaptic loss is an important pathological phenomenon that accompanies Alzheimer's disease
.

Dendritic reduction and damage to cells is also thought to be associated
with toxicity of amyloid hydrolysates.

The results of the trial found that in the brains of early Alzheimer's disease patients, with the development of the disease process, the patient's brain volume decreased, the S1R increased and MC1 decreased, and the expression of the presynaptic vesicle binding protein SV2A was also greatly reduced
.

The regions with the greatest reductions were in the caudal nucleus (-25%, P=0.
07), the hippocampus (-24%, P=0.
001), and the thalamus (-19%, P=0.
012).


However, the specific time at which SV2A expression reduction occurs in the disease process and its rate relationship with the disease process remains to be studied
.

Relationship between changes in MC1 and SV2A expression in the hippocampus of patients with Alzheimer's disease (red line) and healthy volunteers (gray line).

The study, a multi-model molecular marker experiment in vivo, found that elevated oxidative stress responses
were widespread in the early Alzheimer's brain.

Although the study still has some limitations and deficiencies, such as a small sample size and a single marker, its results provide important evidence
for the relationship between mitochondrial oxidative stress and endoplasmic reticulum stress in the brain in early Alzheimer's disease.

This study also proves that although there are differences in brain regions, cellular stress in Alzheimer's disease is widespread in various brain regions
.

Compared with studies that target specific brain regions, this study provides more potential pathological mechanisms and targets for subsequent Alzheimer's disease treatment and early intervention
.

In the field of Alzheimer's disease research, the evidence of in vivo research in the early stage of the disease can not only help researchers better understand the pathogenesis, but also provide potential references and markers for early screening and prevention of the disease, so that everyone has more time and treatment strategies
to deal with Alzheimer's disease.

Resources:

[1] Hardy J, Allsop D.
Amyloid deposition as the central event in the aetiology of Alzheimer's disease.
Trends Pharmacol Sci.
1991; 12(10):383-388.
doi:10.
1016/0165-6147(91)90609-v [2] Hardy JA, Higgins GA.
Alzheimer's disease: the amyloid cascade hypothesis.
Science.
1992; 256(5054):184-185.
doi:10.
1126/science.
1566067

[3] Scheltens P, De Strooper B, Kivipelto M, et al.
Alzheimer's disease.
Lancet.
2021; 397(10284):1577-1590.
doi:10.
1016/S0140-6736(20)32205-4 [4] Tönnies E, Trushina E.
Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease.
J Alzheimers Dis.
2017; 57(4):1105-1121.
doi:10.
3233/JAD-161088

[5] Venkataraman AV, Mansur A, Rizzo G, et al.
Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.
Sci Transl Med.
2022; 14(658):eabk1051.
doi:10.
1126/scitranslmed.
abk1051

[6] Mishina M, Ohyama M, Ishii K, et al.
Low density of sigma1 receptors in early Alzheimer's disease.
Ann Nucl Med.
2008; 22(3):151-156.
doi:10.
1007/s12149-007-0094-z

[7] Hedskog L, Pinho CM, Filadi R, et al.
Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models.
Proc Natl Acad Sci U S A.
2013; 110(19):7916-7921.
doi:10.
1073/pnas.
1300677110

The author of this article Shi Anqi

Editor-in-charge Daisi Rain