Profiling of microglial-originated microvesicles to unearthing their lurking potential as potent foreseeable biomarkers for the diagnosis of Alzheimer's disease: A systematic review

Abstract

Background: Alzheimer's Disease is a neurodegenerative disease characterized by accumulation of phosphorylated tau and amyloid deposits within the brain tissues in the elderly population. Numerous studies established that amassment of these toxic accretions within the brain tissues initiates neuronal demise and synaptic impairment which becomes the underlying basis for memory loss and cognitive abnormalities in these patients.

Hypothesis: Hypoxia, oxidative stress, and inflammation are commonly encountered perils in the neuronal milieu that derail the neuron-synapse interactions and maneuver them to undergo apoptosis. A spinoff from neuronal desecration is microglial activation which forms a cardinal role in mounting innate immune defenses for warding off and reversing off toxic stimulus encountered.

Results: A potential ramification of microglial activation in this context is assembly, processing and exuding of micro-vesicles into the extracellular space. These micro-vesicles will be packaged with amyloid and tau deposits which accumulate intracellularly within microglial cells secondary to their professional scavenging function. These microglial MVs are prone to seed tau and amyloid beta into the surrounding neuron-synapse framework, thus are implicated in spreading the disease pathology in AD.

Conclusions: Therefore, these MVs can be considered as an omen for disease initiation, progression, monitoring as well gauging the treatment response in the clinical AD cohorts. We speculate future research studies to unmask the dormant potential of these microglial MVs as reliable markers for diagnosis, evaluating the disease progression as well as treatment in AD. This will open the door for early diagnosis of AD so as to prioritize management and optimize clinical outcomes..

Keywords: Activation; Alzheimer’s disease; amyloid beta; biomarkers and neuronal microvesicles; microglia; microvesicles; neurodegeneration; neuronal death; tau.

Figure 1

Microvesicles (MVs) assembly and release: MVs will be assembled within the cytoplasm of the microglial cells and packaged with necessary protein, DNA, RNA, enzymes, microRNAs, and other factors. Their lifecycle transitions from early endosome, late endosome to multivesicular bodies containing numerous cargos. These Mulvetisicular bodies (MVBs) fuse with the plasma membrane resulting in the release of MVs from the budding of the plasma membrane. Once released, these MVs carrying their cargo will traverse the extracellular space. Their functional significance mainly comes into play when interacting with neighboring cells including neurons and astrocytes through paracellular communication. Due to this, they might influence the physiological as well as pathological processes in neurodegenerative diseases such as Alzheimer’s disease. mRNAs: MicroRNAs, MV: Microvesicle, MVB: Mulvetisicular bodies

Figure 2

Microvesicles (MVs) modify the amyloid fibrils to be more neurotoxic in Alzheimer’s disease. Insoluble extracellular amyloid will be ingested by wandering microglial cells through phagocytosis and macropinocytosis phenomenon. Once ingested, these amyloid aggregates will be processed through intracellular degradation pathways. As time progresses, these degradation mechanisms will be ultimately overwhelmed so that alternate mechanisms for processing take precedence. In such a context, the synthesis of microvesicles takes place and these nontoxic amyloid aggregates will be packaged within them. As a part of this processing, nontoxic amyloid will be converted into toxic amyloid due to the specific lipid profile of MVs. Ultimately, they get released by budding of microglial plasma membranes. Once the MVs are assembled intracellularly, the final step in their release is through budding from the plasma membrane. Due to this inherent step, MVs tend to harbor some of the key proteins imprinted in the microglial plasma membrane. This gives us the opportunity to identify the origin of these released MVs in the body fluids by profiling microglial transmembrane markers. Once these MVs are released, they traverse the extracellular space and reach the neurons and exude their toxic pileups onto the neurons. By this mechanism, these MVs originated from microglial cells and will be primarily implicated for spreading of disease pathology with the brain tissues. MVs: Microvesicles

Figure 3

Microvesicles spread disease pathology and thus are noteworthy choices for biomarkers in Alzheimer’s disease (AD). With their selective cargo such as amyloid fibrils and tau and paracellular communication, they spread the disease among the neighboring neurons and thus are responsible for aiding the neurodegenerative process in AD. Due to this functional capability, they might provide a harbinger for disease initiation and progression of AD. On top of that, they might also be harnessed for monitoring the disease prognosis as well as gauging the disease response to anti-amyloid medications in these high-risk preclinical and clinical AD cohorts. With few research studies performed so far to grasp their significance, their lurking potential as reliable biomarkers should be efficiently unearthed. This will be the starting point for including them in the armory of foreseeable biomarkers that can precisely forecast the nascent and subtle brain cellular changes symbolizing AD in the elderly cohorts