Infection accelerates the progression of Alzheimer's disease! Neurology bulls come up with new hypotheses

*For medical professionals only

When Eros Alzheimer's reception in 1901 was of a woman named August Dent who had been admitted to a psychiatric hospital for memory impairment and gibberish, he probably did not expect that his name would be remembered by history for the woman's illness

Alzheimer's disease (AD), the most affected neurodegenerative disease today, was first reported by Dr.

However, researchers have gradually discovered that a variety of other factors are also involved in the pathogenesis of AD, including infectious factors

Recently, Professor Tamir Ben-Hur's team from the Hebrew University in Israel published a blockbuster review in the journal Molecular Neurodegenerative Diseases[4], fusing infectious factors with the traditional Aβ theory, and proposing a corresponding hypothesis: infection can be achieved through bacterial amyloid and other pathogen-related molecular patterns (PAMP, which refers to the presence of some human hosts on the surface of pathogenic microorganisms, but a structurally constant and evolutionarily conservative molecular structure common to many related microorganisms.

Screenshot of the first page of the paper

Amyloid deposition is a necessary inadequate condition for AD to occur

In fact, until now, the amyloid hypothesis is still the mainstream theory to explain the pathogenesis of AD, but many studies have questioned this hypothesis

These studies suggest that amyloid deposition may be necessary for the onset of AD, but not sufficient to cause neurodegenerative death, i.

In addition, the clinical drugs developed for Aβ have been compromised one by one in clinical trials, which has also prompted scientists to look for new targets for AD treatments

Association of systemic infection with AD

The association of systemic infectious factors with AD has a long history, and there is growing evidence of a link between systemic infection and AD, and several studies have shown a significant association between systemic infection and long-term cognitive decline in patients with AD [7, 8].

Systemic infection is associated with cognitive function in patients with AD

But how does systemic infection contribute to the development of AD? This brings us to the Blood-Brain Barrier (BBB

Scientists have found that in the early days of AD, BBB was destroyed
.

Neuroimaging studies in patients with mild cognitive impairment and early AD have shown that disruption of BBB occurs in the hippocampus and multiple gray matter and white matter regions before brain atrophy or symptoms of dementia occur [9, 10], and that BBB integrity in transgenic AD mouse models is compromised early, even before amyloid deposition [11].


Disruption of early AD BBB allows infected pathogens, or PAMP, to invade and affect the central nervous system [12].


 

Periodontitis with AD

For example, one of the recognized infection-related causes of AD is periodontitis
.

Prospective studies have shown that periodontitis is associated with increased pro-inflammatory status and decreased cognitive function in patients with AD [13], and there are three underlying mechanisms
.

First, periodontitis causes the local production of inflammatory factors that are able to enter the circulation and then penetrate the dysfunctional BBB to reach the central nervous system
.

Second, studies have shown that periodontitis's stimulation of the trigeminal nerve may induce the central nervous system to produce cytokines through nerve conduction, which has a synergistic effect on Aβ-activated microglia and promotes the development of AD [14].

A third mechanism is the endotoxin released by the pathogen causing periodontitis (the main component of the cell wall of Gram-negative bacteria) entering the central nervous system through BBB[15], which leads to inflammatory activation by activating TLR4 on the surface of immune cells, including microglia[16], exacerbating the progression of AD brain pathology, particularly the production and aggregation of Aβ and the hyperphosphorylation of Tau [17, 18].

Intestinal flora with AD

Another systemic infectious factor that may be associated with AD is the gut microbiota
.

There are more microbes in the gut than in the brain as a whole [19].


Studies have shown that compared with age- and sex-matched people, the gut microbiome of patients with AD changes significantly, a significant reduction in microbial diversity, and a significantly different composition [20].

In addition, studies in transgenic AD mouse models have shown that intervention by gut microbes can reduce brain amyloid deposition and reduce neuroinflammation [21].


These studies all suggest that the gut microbiota may have an impact on
the occurrence and development of AD.

The intestinal flora is closely related to AD

Gut microbes can produce TLR2 agonists (TLR2 is a receptor for Aβ-induced microglia activation[22]), such as liposulpholipidic acid, which may play a role in the pathogenesis of microcosmic activation of microglia neurotoxic activation, inhibiting TLR2 downstream signals to prevent the progression of AD pathology and the death of neurons in AD transgenic mice [23].

In addition to inducing inflammation of the central nervous system, the gut microbiome can also directly lead to the deposition
of Aβ.

Gut gram-negative bacteria secrete curli protein, which is structurally similar to pathological Aβ and strongly activates immune cells and induces an antimicrobial response [24].


When deposited in the brain, this bacterial amyloid protein is recognized by native immune cells as PAMP, activating immune cells through Toll-like receptor 2 (TLR2) and CD14, promoting neuroinflammation [25].

Given the similarity of Aβ and bacterial amyloid Curli, it has been proposed that Aβ is an antimicrobial polypeptide, and that pathological Aβ deposition in the AD brain may be a defensive, antibacterial response of the brain's inherent immune system [26].


Brain-derived Aβ captures and neutralizes invading pathogens, and its oligomerization is a critical step in leading to AD, and may also be to promote its antimicrobial activity [27].


 

Pathogens that directly invade the brain with AD

In addition to systemic infections, pathogens that directly invade the brain may also play a key role in the development of AD, such as herpes simplex virus (HSV), cytomegalovirus, fungi, and bacteria [4
].

The most studied of these is HSV
.

Levels of HSV1 DNA in the brains of patients with AD are significantly elevated compared to healthy age-matched people [28], and pathological features typical of AD such as abnormal deposition of Aβ and Tau proteins have been observed in patients infected with HSV1, and decreased after antiviral therapy [29].


Consistently, epidemiological studies have shown that the reactivation of HSV1 (the presence of anti-HSV IgM and IgG antibodies) doubles the risk of AD compared to the presence of anti-HSV antibodies alone [30].

Another piece of evidence that HSV1 may play a key role in the pathogenesis of AD is that HSV1 virus tends to invade the olfactory cortex and temporal lobe of the brain, consistent with regional localization of pathological changes in early AD [31].


This suggests a possible pathogenic role
of HSV1 infection in the early stages of AD.

In fact, olfactory disorders are one of the earliest clinical symptoms of AD[32], with pathogens possible entry into the central nervous body system through the nasal-olfactory nerve-olfactory bulb-intraostorhinal cortex,[33] and HSV1[34], Chlamydia pneumoniae[35], and SARS-CoV-2 (coronavirus) can be observed in human olfactory bulbs [36].


The number of people infected by the new crown virus in the global pandemic can be very frightening, and if it really plays an important role in the occurrence and development of AD, it will have disastrous consequences in a few decades
.

Infection and Aβ deposition form a vicious circle

The above studies have strongly shown that infection can aggravate the progression of AD brain amyloid plaque pathology through bacterial amyloid and other PAMP methods, but at the same time, pathological changes in the AD brain also play a key role in the increased sensitivity of the central nervous system to infectious factors, and this process is likely to be the result
of a combination of chronic Aβ deposition-induced neuroinflammation and damaged BBB.

In a vicious cycle of the two, damaged BBB allows the microbiome PAMP to penetrate the central nervous system, promoting neuronal death, which ultimately leads to the onset
of AD.

For this view, Professor Tamir Ben-Hur's team has obtained some evidence in previous studies, such as that in AD mice with BBB damage, PAMP induces neuron degeneration in the brain, but in mice with normal BBB, PAMP does not cause neuronal death [37].

Notably, while most current research on the etiology of AD infection has focused on a single pathogen, there is growing evidence to support the hypothesis that
multiple microbes cause AD.

Therefore, cumulative exposure to multiple pathogens may increase the "burden of infection", leading to the development of AD [4].

Fusion of Aβ and the infectious hypothesis of AD: The deposition of Aβ leads to an increase in the susceptibility of the central nervous system to systemic infections from the systemic environment and PAMP, while the source of infection and PAMP aggravate the pathology of AD and the death of neurons, leading to a vicious circle
.

In this review, the researchers highlight the role of infection and its products in the pathogenesis of AD, and propose a synergistic hypothesis that the Aβ and infectious hypotheses occur and develop in AD
.

Amyloid deposition itself may not lead to neurodegeneration, but it can lead to increased
sensitivity of the brain to the neurotoxic effects of infectious substances.

Under this mechanism, infection-derived PAMP-induced neurodegeneration may be hidden, as it tends to occur in brain regions that have already exhibited significant microglia hyperplasia and pathological changes in AD, which has led scientists to ignore their role
.

For people with AD and their families, the most distant distance in the world may not be just life and death, but the person who was once the most familiar and closest in front of them, but can't remember his or her name
.

We sincerely hope that the research of AD will make breakthroughs as soon as possible, find corresponding therapeutic targets, and bring dawn
to these patients and their families.

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The author of this article Zhu Junhao

Responsible editor dai siyu