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Molecular Relationship between Autism and Alzheimer’s—Implication for Novel Treatment

Autism is a neurodevelopmental disorder characterized by behavioral symptoms, such as delayed speech and language skills, as well as physical traits, like enlarged head circumference. The signs and symptoms of patients with autism is extremely broad, hence the name Autism Spectrum Disorder. Individuals with autism are shown to have higher comorbidity of other disorders like schizophrenia and epilepsy than the general population (Doshi-Velez et al., 2014). But there is a lack of research in the scientific field revolving the comorbidity of autism and Alzheimer’s disease. This paper aims to investigate the molecular relationship and convergent pathways shared between Autism Spectrum Disorder (ASD) and Alzheimer’s Disease (AD). Alzheimer’s is characterized by beta amyloid plaques that break down neurons, leading to memory loss and cognitive dysfunction. A significant etiology shared by ASD and AD is neuroinflammation and aberrant synaptic plasticity. These features can be caused by abnormalities in protein synthesis, such as the amyloid precursor protein (APP), mutations in microglia-related genes, and epigenetic changes to genes like RELN or other transposable elements (TE’s). Ultimately, deeper understanding of the intricate molecular pathways of autism and Alzheimer’s could have novel implications for future research related to early-diagnostic techniques and improved medication for both.

Amyloid Precursor Protein

Amyloid precursor protein (APP) is a membrane protein in brain cells mostly found in the synapse of neurons. Its functions include directing synaptogenesis and neural maturation, and the generation of amyloid (Lahiri et al., 2013). APP is cut in 2 different ways in the brain—one is by alpha-secretase—which leads to the production of sAPPα, p3, and AICD—and the other is by beta-secretase—which results in the production of sAPPβ, Aβ, and AICD (Murphy and LeVine, 2010). Overproduction of beta-amyloid (Aβ) leads to the formation of irremovable plaques seen in Alzheimer’s patients. But on the other hand, overproduction of sAPPα can cause white matter overgrowth, increasing risk of autism endophenotypes like regression (Sokol et al., 2019).


In autism, cell adhesion dysfunction can lead to macrocephaly due to brain enlargement (Aylward et al., 1999, 2002; McCaffery and Deutsch, 2005). Aberrant cell migration and increased cell proliferation also contributes to the weak cell adhesion in autism brains. Consequently, the macrocephaly and weak connections between different parts of the brain leads to intellectual dysfunction and other phenotypes, such as social communication challenges and repetitive behaviors (Lahiri et al., 2013). This pro-growth and anti-pruning neural activity in the brain is one major contributor to abnormal long-term potentiation, the process by which learning and memory occurs through synapse strengthening. Without effective long-term potentiation, there is also intellectual and cognitive dysfunction. These autism endophenotypes are caused by the anabolic pathway of increased sAPPα production (Ray et al., 2011). sAPPα has neurotrophic properties, but too much overgrowth of cranial neurons can result in neurological and behavioral problems (Lahiri et al., 2013).


There are several different pathways through which sAPPα can contribute to brain overgrowth. APP works in opposition of glutamate receptors NMDA and AMPA; while these glutamate receptors inhibit dendritic outgrowth, APP blocks that inhibition (Mattson and Furukawa, 1998). Since APP is located at neuron synapses and plays a role in neurogenesis and migration, it causes the aberrant cell adhesion in autism brains (Lahiri et al., 2013). Another way APP leads to neuronal overgrowth and inflammation is from its regulation by FMRP and mGluR5 (Westmark and Malter, 2007). This was proven through several studies of Fragile X Syndrome, a genetic disorder having high comorbidity with autism. In these studies, researchers found that excessive mGluR5 signaling in the absence of FMRP led to increased seizures, elongated and immature dendritic spines, and cognitive delay (Bear et al., 2004). Loss of FMRP function and enhanced mGluR5 signaling in FXS individuals resulted in higher levels of sAPPα, and contributed to the aggression, seizures, and intellectual deficit as seen in autism patients (Lahiri et al., 2011). Moreover, sAPPα is associated with ADAM17, a protein with “anti-pruning” and cell proliferation activity (Gooz et al., 2009; Lin et al., 2012). sAPPα also ignites aberrant microglia production and function; since this glial cell is responsible for neuronal clearance, abnormal debris clearance can lead to symptoms of autism. Microglia will be further investigated later in this paper. Ultimately, autistic individuals are proven to display a higher level of total plasma sAPPα, and severely autistic patients also showed decreased levels of Aβ40 and Aβ42—proteins known for cell adhesion and neurite pruning (Lahiri et al., 2013).


Epigenetics—a study of gene expression modifications, such as chromatin remodeling or histone modification, without explicit genetic code changes—explains the multitude of pathways through which increased sAPPα can lead to increased risk of autism. The epigenetic LEARn—latent early-life associated regulation—model can further explain how high levels of sAPPα activate neuronal overgrowth and inflammation, which increase brain volume in early life (Lahiri et al., 2013). One path through which sAPPα increases neuroproliferation is through the Akt/PI3K/mTOR path. sAPPα induces cell proliferation through PI3K and mTOR, and activates Akt—a protein involved in cell proliferation, cell migration, transcription, and apoptosis. Akt’s anti-apoptotic, pro-growth, and anti-pruning activity occurs because of sAPPα (Sokol et al., 2019). It is important to note that the PTEN mutation—found in brain tumors, macrocephaly, and autism individuals—regulates PI3K (Lahiri et al., 2013). These three protein—PI3K, mTOR, and Akt—increase the amount of oligodendrocyte progenitors through activation of rho GTPase; this increase in oligodendrocyte production results in hypermyelination. Hypermyelination is significant because white matter in the brain is composed of the myelinated axons of neurons, so an increase in sAPPα is associated with the increased white matter of children with autism (Sokol et al., 2019). Beyond genetic components, the Akt/PI3K/mTOR pathway can be affected by epigenetic DNA methylation levels that either silence or enhance the path (Lahiri et al., 2013).


In contrast with APP’s role in autism, the alternate catabolic amyloid production pathway is indicative of Alzheimer’s Disease. An increase in sAPPβ production is what creates amyloid plaques in the brains of AD patients and contributes to cortical and hippocampal atrophy and fronto-temporal dementia in Alzheimer’s patients (Kumar et al., 2020). Studies have implicated maltose-binding protein (MBP), an important protein in the production of myelin, in possibly playing a role in the treatment of Alzheimer’s or autism. This is because a reduction of MBP may lead to increased beta-amyloid and brain atrophy of AD, while increased MBP may lead to brain growth of ASD; therefore, reversing its role in either case may suggest novel treatments (Sokol et al., 2019). Beta-amyloid is not typically seen in rich white matter, while the rich white matter in autism patients’ brains—caused by cell adhesion dysfunction and aberrant cell proliferation and growth—results in ASD endophenotypes. Future investigation of proteins and epigenetic variables affecting the inversely related alpha- and beta-APP production pathway can help pave the way for scientific advancement in both the autism and Alzheimer’s fields.

Microglia

Microglia are cells known as the “macrophages of the brain;” they degrade neuronal debris and dead or impaired neurons to maintain the health of the CNS. Microglia play four essential roles in the CNS; they survey and monitor through phagocytosis, synaptic pruning, programmed cell death, and neuronal plasticity. For example, mouse models show that during the critical period of synaptic refinement, microglial lysosomes contained pre- and postsynaptic structures (Salter and Stevens, 2017). Previously thought to have a one-dimensional function, microglia are now shown to be correlated in the development of different neurodevelopmental and neurodegenerative diseases, such as autism and Alzheimer’s.


Abnormal microglia activity correlates with ASD endophenotypes in several different ways. Studies show that patients with autism have aberrant microglial number and function in the dorsolateral prefrontal cortex that controls executive function (Morgan et al., 2010). Some individuals with autism have different expression of microglia-related genes, like markers related to inflammation. This is significant since a phenotype of autism is neuroinflammation and increased white matter tracks. Microglia impact inflammatory cytokines and molecules—such as interleukins or tumor necrosis factors (TNF)—that affect synaptic plasticity, which can lead to the altered pruning of cortical synapses (Salter and Stevens, 2017). Dysregulated or overactive synaptic pruning during a child’s critical period of development can lead to aberrant synapse loss and dysfunction, which are manifestations of autism. Additionally, changes in microglial number or function during development can lead to aberrant neuroplasticity in adulthood, which affects long-term potentiation and other learning and memory pathways (Salter and Stevens, 2017). Microglia dysfunction is also enhanced through elevated sAPPα plasma levels (Lahiri et al., 2013). One limitation is that human genetic studies have not yet implicated microglia-expressed genes as a cause for ASD; dysfunctional microglia could be a reaction to injury in other cells like neurons or astrocytes, thereby facilitating the neuronal and circuit dysfunction in autism (Salter and Stevens, 2017).


In contrast, microglia are directly implicated in the etiology of Alzheimer’s. Genome-wide association studies (GWAS) show 20 loci linked to AD, several of which are expressed or exclusively expressed in microglia (Salter and Stevens, 2017). Alzheimer’s pathology—tau aggregates and amyloid-beta plaques—activate microglia, which are responsible for their clearance. Additionally, microglia and AD pathology activate astrocytes, glial cells in the brain that help form the blood-brain barrier (Salter and Stevens, 2017). Amyloid accumulation in blood vessels can lead to vascular damage. Microglia, astrocytes, and the damaged vasculature release cytokines and pro-inflammatory mediators—like IL-1β, TNF-α, and IL-18—and generate reactive oxygen species (Heneka et al., 2015). The secretion of inflammatory molecules triggers phagocytic clearance of Aβ and tau by microglia, and this chronically activated microglia and astroglia exacerbate excessive synaptic pruning and neurodegeneration (Heneka et al., 2018). Also, tissue injury causes the release of damage products, which enhance the proinflammatory environment. Peripheral immune cells are recruited in the AD brain, and proinflammatory mediators from the periphery can aggravate neuroinflammation too (Heneka et al., 2015).


Research surrounding microglia’s role in neurological disorders has already made substantial strides in clinical diagnoses and treatments. Using microglia’s biomarkers—like soluble TREM2 or complement components in cerebrospinal fluid—can allow for earlier detection of at-risk Alzheimer’s individuals than just using symptomatic neuronal dysfunction (Salter and Stevens, 2017). Additionally, the discovery of induced pluripotent stem cells (iPSCs) has opened the door for novel therapeutic results and treatment discoveries. iPSCs—which possess the ability to mimic another cell in the body—allow us to use stem-cell derived brain tissue to view cell biology, like how AD risk cells look different from control cells, and test therapeutic discoveries, such as finding factors that make patient cells look increasingly similar to control cells. With genome editing and evolving stem cell biology techniques like CRISPR-Cas9, we can compare microglia-expressed genes between patients and controls ex vivo, and test genome-editing methods to relieve neuroinflammation and other symptoms of neurological diseases.

RELN Gene in ASD

Other genes have been connected to the etiology of neurological disorders like autism and Alzheimer’s. The RELN gene, located on chromosome 7q22, translates to the reelin protein, which is expressive in GABAergic interneurons in the cortex (Lammert and Howell, 2016). The protein guides migration of cortical neurons, promotes extension of dendritic processes and learning, maturation of dendritic spines, and—in adult brains—facilitates modulation of synaptic function (Lammert and Howell, 2016). Reelin’s functions make it a prime candidate to contribute to the synaptic disruption in autism. Studies show that ASD patients show decreased expression of RELN transcript and encoded protein (Lammert and Howell, 2016). Compared to controls, ASD individuals showed decreased reelin, RELN mRNA, and dab1transcript in the cerebellum and superior frontal cortex (Lammert and Howell, 2016). This is significant since the cerebellum has been implicated in the occurrence of autism, as damage to the cerebellum during development can result in cognitive and communication deficits (Lammert and Howell, 2016). But the genetics of the RELN mutation suggest that there are environmental factors that alter epigenetics and activate DNA methylation levels necessary for ASD (Lammert and Howell, 2016). This could include early life adversaries and other childhood trauma.

Transposable Elements

Transposable elements are genes that make up approximately half our genome. TE’s, also called jumping genes, can be moved across our genome, hence possessing the ability to create or reverse mutations. They can be subject to silencing or expression by epigenetic effects like DNA methylation, histone methylation, and other forms of chromatin remodeling. In autism, the activated immune system stems from a dysregulated immune response from the periphery as well as microglia and astrocyte activation in the brain (Jönsson et al., 2020). TE’s are known to activate immune pathways, creating theories about their involved in autism. For example, in AGS, a disease characterized by severe neurological impairments, mutations in genes from the accumulation of TE-derived cytosolic nucleic acids activate the innate immune system, which is similar to the inflammatory response in autism (Jönsson et al., 2020). In other words, TE’s misinterpreted as viral infections by the host cell can result in inflammation. Transposable elements also play a role in Alzheimer’s. As people age, TE’s become more active, which can increase risk of mutations. DNA methylation levels also increase as people age (Jönsson et al., 2020). These epigenetic changes may result in the activation of TE’s. In Alzheimer’s, overexpression of the tau protein can lead to a global loss of heterochromatin which activates TE expression. Investigation into transposable elements has already led to novel research. In Drosophila AD models, disease-related phenotypes were restored by blocking TE activity through the use of reverse transcriptase inhibitors (Jönsson et al., 2020). Furthermore, recent evidence shows that APP copies could be undergoing somatic transposition and copy number expansion in AD brains (Jönsson et al., 2020). Therefore, by using TE’s expressing reverse transcriptase, like LINE-1 elements, we can potentially mediate the overproduction of amyloid-beta plaques in Alzheimer’s Disease patients (Jönsson et al., 2020).


Conclusion


With recent advancement in science and technology, autism and Alzheimer’s etiology have become increasingly convergent. Many phenotypes from these two neurological disorders stem from abnormality in the same proteins and pathways. In the APP production pathway, higher sAPPα plasma levels increase the risk of ASD endophenotypes, while greater production of sAPPβ leads to the accumulation of damaging amyloid-beta plaques of Alzheimer’s pathology. Additionally, aberrant microglia can lead to neuroinflammation, which excessively prunes synapses and leads to region-specific changes in dendritic branching, spine density, and neural connectivity. Furthermore, genes like RELN and other transposable elements have been implicated in AD and ASD, and research shows that silencing specific genes can reverse disease-related phenotypes. Ultimately, continuous research into the neural intricacies of autism and Alzheimer’s allows us to piece together the relationship between the two and utilize knowledge from both fields to design novel treatments.




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