Much of the research on the underlying causes of Alzheimer’s disease focuses on amyloid beta (Aß), a protein that accumulates in the brain as the disease progresses.
Excess Aß proteins form clumps or “plaques” that disrupt communication between brain cells and trigger inflammation, eventually leading to widespread loss of neurons and brain tissue.
Aß plaques will continue to be a major focus for Alzheimer’s researchers.
However, new work by neuroscientists at the University of Chicago looks at another process that plays an underappreciated role in the progression of the disease.
In a new study published in the Journal of Neuroscience, Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago, and his colleagues show how in genetic forms of Alzheimer’s, a process called neurogenesis, or the creation of new brain cells, can be disrupted by the brain’s own immune cells.
Some types of early onset, hereditary Alzheimer’s are caused by mutations in two genes called presenilin 1 (PS1) and presenilin 2 (PS2).
Previous research has shown that when healthy mice are placed into an “enriched” environment where they can exercise, play and interact with each other, they have a huge increase in new brain cells being created in the hippocampus, part of the brain that is important for memory.
But when mice carrying mutations to PS1 and PS2 are placed in an enriched environment, they don’t show the same increase in new brain cells.
They also start to show signs of anxiety, a symptom often reported by people with early onset Alzheimer’s.
This led Sisodia to think that something besides genetics had a role to play.
He suspected that the process of neurogenesis in mice both with and without Alzheimer’s mutations could also be influenced by other cells that interact with the newly forming brain cells.
Focus on the microglia
The researchers focused on microglia, a kind of immune cell in the brain that usually repairs synapses, destroys dying cells and clears out excess Aß proteins.
When the researchers gave the mice a drug that causes microglial cells to die, neurogenesis returned to normal.
The mice with presenilin mutations were then placed into an enriched environment and they were fine; they didn’t show any memory deficits or signs of anxiety, and they were creating the normal, expected number of new neurons.
He feels that this discovery about the microglia’s role opens another important avenue toward understanding the biology of Alzheimer’s disease. The image is in the public domain.
“It’s the most astounding result to me,” Sisodia said.
“Once you wipe out the microglia, all these deficits that you see in these mice with the mutations are completely restored. You get rid of one cell type, and everything is back to normal.”
Sisodia thinks the microglia could be overplaying their immune system role in this case.
Alzheimer’s disease normally causes inflammation in the microglia, so when they encounter newly formed brain cells with presenilin mutations they may overreact and kill them off prematurely.
He feels that this discovery about the microglia’s role opens another important avenue toward understanding the biology of Alzheimer’s disease.
“I’ve been studying amyloid for 30 years, but there’s something else going on here, and the role of neurogenesis is really underappreciated,” he said.
“This is another way to understand the biology of these genes that we know significantly affect the progression of disease and loss of memory.”
Additional authors include Sylvia Ortega-Martinez, Nisha Palla, Xiaoqiong Zhang and Erin Lipman from the University of Chicago.
Alzheimer’s disease (AD) is a neurodegenerative disorder that is the most common cause of dementia and is characterized by the decline in cognitive and function and neuronal loss. AD currently affects over 5 million Americans [1] and is expected to become increasingly prevalent with the rise in life expectancy.
It is estimated that by 2050, 13.8 million Americans will be living with AD [2]. The financial burden imposed by AD currently exceeds $230 billion and is expected to reach $1.1 trillion by 2050 [3].
Given the clinical and financial burden associated with AD, the identification of novel mechanisms responsible for pathogenesis, as well as novel therapeutic targets, is urgently needed.
AD is characterized by two core pathologies, the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs). Aβ pathology arises from the improper cleavage of the amyloid precursor protein (APP) resulting in Aβ monomers that aggregate forming oligomeric Aβ and eventually aggregating into Aβ fibrils and plaques [4].
The function of APP is unknown but is believed to have a role in cell health and growth [5].
Critical aspects of understanding the onset of Aβ pathology rests on knowing the mechanisms of the generation of Aβ monomers, their clearance, and their aggregation into oligomeric Aβ.
Normal processing of the APP sequence consists of nonamyloidogenic proteolysis of APP via α-secretase and λ-secretase, producing soluble fragments [6].
When APP is cleaved by λ-secretase and erroneous β-secretase, it leads to insoluble amyloid β peptides that aggregate in the brain to form β-amyloid plaques [4], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. The precise role of Aβ in AD pathology remains an open question as Aβ plaques may accumulate up to 10 years before any observable AD symptoms or diagnosis.
The second core pathology, NFT, arises from the hyperphosphorylation of tau, a microtubule-associated protein that stabilizes microtubules [18], [19], [20], [21], [22], [23], [24], [25], [26], [27].
Phosphorylation of tau serves a necessary role in intracellular trafficking to remove tau from microtubules, allowing transport, followed by dephosphorylation to return tau to the microtubule [28].
In AD, tau protein is phosphorylated at multiple sites resulting in the removal of tau from the microtubule and causing the collapse of microtubule structures and disruption in a number of cellular processes ranging from protein trafficking to overall cellular morphology [29], [30], [31].
In addition, the hyperphosphorylated tau (ptau) aggregates into paired helical fragments that eventually form neurofibrillary tangles [20], [24], [25], [32], [33]. The accumulation of ptau tangles and the compromised cellular function leads to loss of neuronal function, and ultimately apoptosis [30].
Despite extensive and productive research investigating the mechanisms responsible for both core pathologies, as well as approaches aimed at the prevention of Aβ plaques and NFT, there remains no treatment that effectively alters either pathology in clinical populations [34].
Furthermore, there exists a considerable gap in the understanding of AD pathogenesis given these two pathological features.
As stated previously, patients may exhibit Aβ plaque pathology for up to or greater than a decade before any overt diagnosis of AD [35], [36]. For NFT, the overall tangle load is correlated with cognitive decline in AD; however, the appearance of NFT appears to occur before the inauguration of AD pathology in clinical populations and preclinical animal models [37], [38], [39].
The combination of the aforementioned gaps in the pathophysiology of AD suggests that other pathological mechanisms may be driving both the onset of the disorder, as well as the progression of the disease.
Over the last 10 years, a third core feature of AD has emerged that may provide insight into AD pathogenesis, as well as provide a link between the other two core pathologies.
A number of investigations initially demonstrated that in addition to Aβ plaques and NFT, the brains of patients with AD exhibited evidence of a sustained inflammatory response [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50].
The inflammatory response has now been observed in multiple studies of postmortem tissues of AD patient samples [51], [52], [53], [54], [55], [56], [57] and is routinely observed in preclinical model systems of AD.
Acute inflammation in the brain is a well-established defense against infection, toxins, and injury, but when a disruption in the equilibrium of anti-inflammatory and pro-inflammatory signaling occurs, as seen in AD, it results in chronic inflammation (neuroinflammation) [58], [59], [60], [61].
This chronic neuroinflammation is attributed to activated microglia cells and the release of numerous cytokines.
The presence of a sustained immune response in the brain is not exclusive to AD. A number of studies have demonstrated elevated markers of inflammation in the brain of patients with Parkinson’s disease (PD) [62], [63], [64], [65], [66], and traumatic brain injury associated with chronic traumatic encephalopathy (CTE) [67], [68], [69], [70], amyotrophic lateral sclerosis (ALS) [70], and Multiple Sclerosis (MS) [71] to name a few key examples. It is increasingly recognized that a sustained immune response is a central feature of neurodegenerative disorders [71], [72], [73], [74], [75], [76], [77].
The presence of a sustained inflammatory response in the brain of patients with AD was, at one point, thought to be reactive to the neuronal loss occurring in the disorder. However, substantial body of research has now demonstrated that a persistent immune response in the brain is not only associated with neurodegeneration but it also facilitates and exacerbates both Aβ and NFT pathologies.
Furthermore, it has been suggested that the inflammatory response may provide a link between the initial Aβ pathology and the later development of NFT [78], [79], [80], [81], [82], [83].
In the succeeding sections, we highlight some of the recent data indicating the role of inflammation in AD, as well as data indicating inflammation may be a central mechanism driving Aβ pathology and progression.
This review highlights the research supported by the National Institutes of General Medical Sciences (NIGMS) through Center for Biomedical Research Excellence (COBRE) awards that develop the national research infrastructure.
Inflammation in AD
Many studies now point to the involvement of neuroinflammation playing a fundamental role in the progression of the neuropathological changes that are observed in AD. Since the 1980s, there have been reports of immune-related proteins and cells located within close proximity to β-amyloid plaques [43], [84].
Beginning in the 1990s, several large epidemiological and observational studies were published indicating that anti-inflammatory treatments used in diseases, such as rheumatoid arthritis, showed protective qualities against developing AD, demonstrating as much as a 50% reduction in the risk for developing AD in patients who are long-term nonsteroidal anti-inflammatory drug (NSAID) users [77], [85], [86], [87].
These studies lead to studies utilizing animal transgenic AD models demonstrating that NSAIDs can reduce AD pathology [88]. Human trials of NSAIDS showed variable outcomes with no convincing evidence of benefit using the trial methods of the time [89].
These various epidemiological studies and observational studies serve as the bedrock of support for neuroinflammation playing a major role in developing sAD. Unlike other risk factors and genetic causes of AD, neuroinflammation is not typically thought to be causal on its own but rather a result of one or more of the other AD pathologies or risk factors associated with AD and serves to increase the severity of the disease by exacerbating β-amyloid and tau pathologies [90], [91].
Brain inflammation appears to have a dual function, playing a neuroprotective role during an acute-phase response, but becomes detrimental when a chronic response is mounted [92].
Chronically activated microglia release a variety of proinflammatory and toxic products, including reactive oxygen species, nitric oxide, and cytokines.
In deceased patients suffering from recent head trauma, there is an increase in cerebral Aβ deposits 1–3 weeks postinjury, and it has been shown that elevated levels of interleukin 1 (IL-1) are responsible for the increased APP production and Aβ load [93], [94].
In addition, elevated levels of IL-1β has been shown to increase the production of other cytokines, including IL-6, which in turn has been shown to stimulate the activation of CDK5, a kinase known to hyperphosphorylate tau [95].
The neuroinflammation observed in AD appears to serve a primary role in exacerbating Aβ burden and tau hyperphosphorylation, suggesting that this dual role could be a leading link between these seemingly disparate core AD pathologies. The mounted immune response via the brain’s resident macrophage (microglia) is now a central tenant in the investigation of AD.
Microglia
Microglia are the resident immune cells within the central nervous system (CNS) [96].
In a healthy brain, microglia are in an inactive, “resting” state and are described morphologically as ramified cells with small somas [97], [98].
In this state, the cell somas are stationary, while the cell processes extend and retract, surveying their environment and communicating with neurons and other glia cells [99], [100], [101].
Overall surveillance of the surrounding neuronal environment is accomplished via a large number of signaling mechanisms [99], [102].
This includes surveillance of the local neuronal milieu via numerous receptors for classical neurotransmitters [103], receptors for numerous cytokines and chemokines [104], [105], [106], and a number of receptors, such as fractalkine (CX3CR1), that bind ligands constitutively released in healthy neuronal environments [107].
When microglia recognize a threat to the CNS, such as invasion, injury, or disease, it leads to microglial activation, causing a morphological change resulting in retraction of processes, enlargement of the cell, and migration [99], [108], [109], [110], [111].
Transitioning into an activated state may be triggered by alterations in any number of the aforementioned mechanisms involved in surveillance.
In AD, it is hypothesized that the primary driver of activation of microglia is the presence of Aβ.
Activated microglia respond to Aβ resulting in migration to the plaques and phagocytosis of Aβ [108], [112], [113].
A number of investigations have demonstrated that activated microglia phagocytose Aβ [114], [115], [116], [117]; however, these microglia become enlarged and after prolonged periods are no longer able to process Aβ [114], [118].
Early in AD pathogenesis, the mounted immune response results in clearance of Aβ and has been demonstrated to exert positive effects on AD-related pathologies in animal models’ systems [77], [119], [120].
However, prolonged activation of the immune response has been demonstrated to result in an exacerbation of AD pathology, likely as a result of sustained activation of microglia in a feed forward loop, referred to as reactive microgliosis.
This results in an accumulation of Aβ and sustained pro-inflammatory cytokine singling beginning to damage neurons [118], [121], [122].
The sustained activation also results in a decrease in microglia efficiency for binding and phagocytosing Aβ and decreases in Aβ degrading enzyme activity of microglia leading, in turn, to a reduced ability to break down the Aβ plaques [123], [124].
However, data indicate that the microglial capacity for producing pro-inflammatory cytokines is unaffected [118].
These data demonstrate a unique feature of pathogenesis in that overall clearance of Aβ becomes compromised while immune activation continues simultaneously.
The continued release of pro-inflammatory cytokines and associated neurotoxins from microglia serves to exacerbate the neuroinflammation and contribute to neurodegeneration, leading to the activation of yet more microglia.
As the microglia are involved in clearance of Aβ, they release a number of proinflammatory cytokines that recruit additional microglia to plaques [125], [126], [127], resulting in a characteristic halo of activated microglia surrounding plaques [112], [128].
More recent data indicate that as microglia become less able to clear Aβ, peripheral macrophages may be recruited to Aβ plaque deposition in an effort to clear Aβ [129].
The recruitment of peripheral macrophages into the brain likely exacerbates the effects of sustained inflammation and thus AD pathology.
Some of the most compelling data for the importance of inflammation in AD pathogenesis and the regulation of the immune response comes from the recent demonstration that a mutation in the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) confers a greater likelihood of developing AD [129], [130], [131], [132]. A rare missense mutation in TREM2 results in a substantial elevated risk of AD [133], [134], [135], [136].
Source:
University of Chicago
Media Contacts:
Matt Wood – University of Chicago
Image Source:
The image is in the public domain.
Original Research: Closed access
“Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer’s Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion”. Sylvia Ortega-Martinez, Nisha Palla, Xiaoqiong Zhang, Erin Lipman and Sangram S. Sisodia.
Journal of Neuroscience. doi:10.1523/JNEUROSCI.0884-19.2019
