Experimental models of Alzheimer's disease

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Experimental methods used to study Alzheimer's disease Cell culture-fig.png
Experimental methods used to study Alzheimer's disease

Experimental models of Alzheimer's disease are organism or cellular models used in research to investigate biological questions about Alzheimer's disease as well as develop and test novel therapeutic treatments. Alzheimer's disease is a progressive neurodegenerative disorder associated with aging, which occurs both sporadically (the most common form of diagnosis) or due to familial passed mutations in genes associated with Alzheimer's pathology. [1] [2] Common symptoms associated with Alzheimer's disease include: memory loss, confusion, and mood changes. [3]

Contents

As Alzheimer's disease affects around 55 million patients globally and accounts for approximately 60-70% of all dementia cases, billions of dollars are spent yearly towards research to better understand the biological mechanisms of the disease as well as develop effective therapeutic treatments for it. [2] [4] Researchers commonly use post-mortem human tissue or experimental models to conduct experiments relating to Alzheimer's disease. [5] Experimental models of Alzheimer's disease are particularly useful as they allow complex manipulation of biological systems to elucidate questions about Alzheimer's disease without the risk of harming humans. These models often have genetic modifications that enable them to be more representative of human Alzheimer's disease and its associated pathology: extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). [6] Current methods used by researchers are: traditional 2D cell culture, 3D cell culture, microphysiological systems, and animal models.

Cell culture models

Cortical Neuron Culture 6DIV 20X (3934022).jpg
Cortical Neuron Culture

2D cell culture

Traditional two dimensional cell culture is a useful experimental model of Alzheimer's disease to conduct experiments in a high throughput manner. These cultures occur on a dish or flask in a monolayer and can be made up of a single cell type or multiple cell types. [7] 2D cultures often have difficulties producing insoluble Amyloid-β plaques even when they are able to secrete the Amyloid-β peptide. [8] [9] Common types of 2D cell culture used to model Alzheimer's disease are immortalized cell lines, primary neuron cultures, and patient derived induced pluripotent stem cells (iPSC).

Immortalized cell lines

Immortalized cell lines are cells from an organism which have been genetically manipulated to be able to proliferate in vitro, making them a useful tool for researchers as they can do so quickly allowing for high-throughput experimentation. These mutations can occur from a natural caused mutation, like those found in cancer cells, or from being introduced by researchers. Common immortalized cell lines used to study Alzheimer's disease include: human embryonic kidney 293 (HEK293), human neuroblastoma (SH-SY5Y), human neuroglioma (H4), human embryonic mesencephalic (LUHMES), human neural progenitor (ReN), and pheochromocytoma (PC12) cells. [10] These types of cells are commercially available, relatively inexpensive, and easy to culture and maintain. [10] [11] Pro-death compounds can be used in these models to induce Alzheimer's disease related cell death. These compounds include: Amyloid-β 42, tau protein, glutamic acid, [12] and oxidative/pro-inflammatory compounds. [13]

Primary neuron culture

Primary neuron cultures are generated from embryonic or postnatal rodent brain tissue and cultured on plates. [14] Common brain regions used for cultures to study Alzheimer's disease include the hippocampus, cortex, and amygdala; however any brain region is suitable for cultures. [7] This method requires dissection of the desired brain region from rodent tissue followed by digestion, dissociation, and plating steps. [14] As these cultures are derived directly from rodent brain tissue, they morphologically and physiologically resemble human brain cells, contain multiple neuronal cell types, and do not proliferate. [10] When initially cultured, these cells are spherical and over time begin to form axons, dendrites, and eventually develop synaptic connections. [14]

Induced pluripotent stem cells

iPSC methods used in Alzheimer's disease research IPSCs redo final.png
iPSC methods used in Alzheimer's disease research

Patient-derived induced pluripotent stem cell (iPSC) lines are unique in which differentiated somatic cells are taken from Alzheimer's disease patients and reverted into pluripotent stem cells via an ectopic transcriptional "Tamanaka" factor cocktail. [11] These stem cells can then be directed to differentiate into many cell types, including neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells. [5] [11] This allows these models to be generated from both early-onset familial Alzheimer's disease (FAD) patients with mutations in APP, PSEN1, or PSEN2 genes as well as late-onset/sporadic Alzheimer's disease (SAD) patients, a population which is not wholly replicated in animal models. As SAD is the most commonly diagnosed form of AD, this highlights iPSCs as key tools for understanding this form of the disease. [5] These cells can also be purchased commercially. [15] [16] CRISPR-Cas9 technology can be used alongside iPSC cells to generate neurons carrying multiple FAD mutations. [5] [10] One major downfall of these models are that they can inadequately resemble mature neurons as well as being more expensive and difficult to maintain. [11] iPSCs have also been shown to exhibit genomic instability and develop additional mutations when passaged (harvested and reseeded into daughter cultures) numerous times, posing both safety concerns for patient use as well as potential reproducibility problems in experimental studies. [5] Due to the nature of reprogramming procedures, iPSC cells lose cellular and epigenetic signatures acquired by aging and environmental factors, limiting iPSCs ability to recapitulate diseases associated with aging, like Alzheimer's disease. While these cultures have some limitations, many fundamental discoveries about Alzheimer's disease biology have been elucidated using this model system.[ citation needed ]

Important Alzheimer's Disease Findings using iPSCs [5]
Cell TypeMutation(s)Importance
Astrocytes
  • Isogenic PSEN1ΔE9
  • Isogenic APOE3 and APOE4
  • PSEN1 astrocytes lacking exon 9 displayed increased amyloid-β production and oxidative stress, decreased neuronal support functionality, and changed calcium homeostasis as well as cytokine release [17]
  • APOE4 astrocytes showed an increase in cholesterol and reduced amyloid-β clearance [18]
MicrogliaIsogenic APOE3 and APOE4APOE4 microglia showed decreased morphological complexity and reduced uptake of amyloid-β from culture media [18]
Neurons
  • SAD, APPDp
  • Down Syndrome
  • Isogenic APOE3, APOE4, APOE null
  • AD neurons from early iPSC experiments showed increased amyloid-β, phosphorylated-tau, and endoscope accumulation [19]
  • Neurons from down syndrome patients (containing triplication of chromosome 21 containing the APP gene) displayed increased amyloid-β secretion and aggregation as well as tau phosphorylation [20]
  • APOE4 neurons showed increased amounts of amyloid-β and phosphorylated-tau and degeneration of GABAergic neurons [21]
3D Cultures
  • Overexpression APPK670N/M671L, APPV717I, PSEN1ΔE9
  • Overexpression APPK670N/M671L, APPV717I, PSEN1ΔE9
  • Accumulation of amyloid-β from these cells caused filamentous tau deposition [22]
  • Neurons, astrocytes, and human microglia co-cultured together replicated AD phenotypes, neuroinflammation, and microglial recruitment [23]

3D organoid culture

Three dimensional organoid culture methods have become a popular way of recapitulating AD pathology in a more "brain-like" environment than traditional 2D culture as they create a organized structure similar to that of the human cortex. [10] [24] This has proven effective specifically for modeling Alzheimer's disease as 2D cultures tend to fail at producing insoluble amyloid-β while 3D culture models are able. [8] These models consist of multiple neuronal cell types co-cultured together in artificial matrices allowing for the understanding of how non-neuronal cells and neuroinflammation influence Alzheimer's disease pathogenesis. [11] The neuronal cell types expressed in these models often include neurons, astrocytes, microglia, oligodendrocytes, epithelial, and endothelial cells. [9] [11] These organoids develop over many months in order to display Alzheimer's pathology and can be maintained for long periods of time. [5] [9] They can be derived from both iPSCs or immortalized undifferentiated cells and typically reach a diameter of several millimeters. [9] [24] 3D cultures can either be allowed to self-organize or be placed under guided formation in which exogenous factors influence the differentiation pattern of the organoid. [9] 3D culture methods have shown more robust Amyloid-β aggregation, phosphorylated-tau accumulation, and endosome abnormalities than 2D culture methods of the same cell lines, indicating accelerated pathology. [5] [24]

Brain-on-a-Chip Microphysiological System.jpg
Brain-on-a-Chip

Common issues arising from the use of 3D cultures is the lack of vasculature within the organoid, leading to cell death and dysfunction at inner layers. [5] [9] Current[ when? ] efforts are focusing on introducing endothelial cells into guided formation cultures in order to create vascular systems and provide nutrient distribution to deep layers. [5] [9] Self-organizing organoids also vary in terms in proportion and location of expressed cells causing challenges in reproducibility of experiments. [9] More effort has been placed on guided formation organoids to account for this problem, however this method is more time consuming and difficult to optimize. [9] 3D organoid culture's ability to resemble aging phenotypes is also limited as many organoid methods rely on iPSCs which are more similar to prenatal brain cells due to reprograming protocols. [9] Researchers are currently[ when? ] investigating common transcriptional profiles associated with Alzheimer's disease and aging in order to reintroduce these landscapes into iPSCs for future biomedical research and therapeutic development.[ citation needed ]

Microphysiological systems

Neuronal microphysiological systems, also referred to as a "brain-on-a-chip," are a combination of 3D cultures and a microfluidics platform, which circulates the media provided to the cultured cells. [10] These devices are beneficial as they improve cell viability and better model physiological conditions as they improve oxygen availability and nutrient delivery to inner layers of 3D cultures. [9] [25] These systems additionally introduce physiological cues such as fluid sheer stress, tension, and compression which allows these in vitro conditions to better resemble the in vivo environment. [8] Microphysiological systems were shown to replicate Amyloid-β aggregation, hyperphosphorylated tau, and neuroinflamation as well as display microglial recruitment, release of cytokines and chemokines, and microglial neurotoxic activation as a response of more physiologically relevant cell-cell interactions. [10] These systems can also be developed incorporating brain endothelial cells to mimic the blood–brain barrier, making this an extremely useful model for BBB dysfunction in Alzheimer's disease, screening novel therapeutics potential to pass from the blood into the brain, therapeutic pharmacokinetics, as well as drug adsorption, distribution, metabolism, elimination, and toxicity (ADMET) tendencies. [8] [10] [25]

Animal models

Rodents

Familial Alzheimer's disease mutations commonly used in animal models FAD Mutations redo final.png
Familial Alzheimer's disease mutations commonly used in animal models

Rodent animal models of Alzheimer's disease are commonly used in research as rodents and humans have many of the same major brain regions and neurotransmitter systems. [5] These models are small, easy to house, as well as breed very well. [26] Mice and rats on average tend to live for 2 years, a much shorter lifespan than humans, presenting both limitations as well as benefits for more rapid experiment completion. [5]

In order to recapitulate and accelerate human Alzheimer's disease pathology, scientists commonly introduce FAD associated mutations. [27] Common genes targeted for genetic engineering in animal models are APP, MAPT, PSEN1, PSEN2, and APOE. [6] This results in the animal models having a higher tendency to form amyloid-β plaques and/or neurofibrillary tangles, the two pathological hallmarks of Alzheimer's disease. [6] These mutated genes can either be over-expressed (first generation models) or expressed at endogenous levels (second generation models) as a way of further replicating disease pathology. [6] Scientists also over-express non-mutated human genes in the hope of seeing similar Alzheimer's disease pathology. [28] These introduced mutations or over-expression of human Alzheimer's associated genes, can lead these animals to additionally display cognitive impairment, deficits in long-term potentiation (LTP), synaptic loss, gliosis, and neuronal loss. As current models are highly reliant on FAD mutations to induce Alzheimer's like pathology, there is still no ideal model that fully replicates SAD (sporadic Alzheimer's disease), which is the most common type of diagnosis in patients. [29]

Common methods used to generate these lines are the use of transgenes controlled by a specific promoter, Cre-Lox recombination, and the CRISPR-Cas9 system. Scientists can also use injection methods such as intracerebroventricular injection, [30] intravenous injection, [31] [32] or intrahippocampal injection [33] to modify wild type rodents into displaying Alzheimer's disease pathology. These rodent models are often used to test and develop drugs treating Alzheimer's disease before progressing to clinical trials in humans.[ citation needed ]

Mouse models

NameGenesModification InformationPromoterKnown Pathology (Age of Onset in Months)
APP Models
APPSwe TgC3-3 [28] [34] APPExpress both murine and human APP carrying the Swedish mutationMurine PrPAβ plaques (24-26 mo)
Tg2576 [28] [35] APPOver-expresses human APP with the Swedish mutationHamster PrPSynaptic loss (4-6 mo), LTP deficits (4-6 mo), cognitive impairment (4-6 mo), gliosis (10-16 mo), Aβ plaques (11-13 mo)
APP23 [28] [36] APPDisplay a 7-fold over-expression of human APP carrying the Swedish mutationMurine Thy1Cognitive impairment (3 mo), Aβ plaques (6 mo), gliosis (6 mo), neuronal loss (14-18 mo)
PDAPP [28] [37] APPOver-express human APP carrying the Indiana mutationPDGFβCognitive impairment (3 mo), LTP deficits (4-5 mo), Aβ plaques (6 mo), gliosis (6 mo), synaptic loss (8 mo)
TgCRND8 [28] [38] APPDisplay 5-fold over-expression of human APP carrying the Swedish and Indiana mutationsSyrian hamster PrPCognitive impairment (3 mo), Aβ plaques (3 mo), gliosis (3 mo), LTP deficit (6 mo), synaptic loss (6 mo), neuronal loss (6 mo)
APPNL-F [39] APPExpress humanized APP with the Swedish and Iberian mutationsN/AAβ plaques (6 mo), gliosis (6 mo), synaptic loss (9-12 mo), cognitive impairment (18 mo)
APPNL-G-F [40] APPExpress endogenous levels of humanized APP carrying the Swedish, Iberian, and Arctic mutationsN/AAβ plaques (2 mo), gliosis (2 mo), synaptic loss (4 mo), cognitive impairment (6 mo)
Tau Models
JNPL3 [28] [41] MAPTExpress 4 repeat human Tau carrying the P301L mutationMurine PrPNeurofibrillary tangles (4.5 mo), neuronal loss (10 mo), gliosis (10 mo)
pR5 [28] [42] MAPTOver-express 4 repeat human Tau carrying the P301L mutationMurine Thy1Cognitive impairment (5 mo), LTP deficits (6 mo), gliosis (7 mo), neurofibrillary tangles (8 mo)
Tau P301S [43] [44] MAPTOver-express human Tau carrying the P301S mutationMurine PrPGliosis (3 mo), synaptic loss (3 mo), neurofibrillary tangles (6 mo), LTP defects (6 mo), cognitive impairment (6 mo), neuronal loss (9-12 mo)
PSEN Models
PS1 M146V [45] PSEN1Over-express PSEN1 with the M146V mutationRat PDGFβNeuropathology is absent in these mice. Cognitive ability has not been observed.
Other Models
TAPP [28] [46] APP, MAPTOver-expression of human APP carrying the Swedish mutation and 4 repeat human Tau with the P301L mutation.Hamster PrP, Murine PrPNeurofibrillary tangles (3 mo), gliosis (3 mo), Aβ plaques (9 mo)
3xTg-AD [28] [47] APP, PSEN1, MAPTExpress human APP with the Swedish mutation, MAPT with the P301L mutation, and PSEN1 with the M146V mutationMurine Thy1 (PS1 knockin)Cognitive impairment (4 mo), Aβ plaques (6 mo), LTP deficits (6 mo), gliosis (7 mo), neurofibrillary tangles (12 mo)
PSAPP [28] [48] APP, PSEN1Over-express human APP with the Swedish mutation and PSEN1 with the M146L mutationHamster PrP, PDGFβCognitive impairment (3 mo), Aβ plaques (6 mo), gliosis (6 mo), neuronal loss (22 mo)
5xFAD (B6SJL) [49] [50] APP, PSEN1Over-express human APP with the Swedish, Florida, and London mutations and PSEN1 with the M146L and L286V mutationsMurine Thy1Aβ plaques (2 mo), gliosis (2 mo), synaptic loss (4 mo), cognitive impairment (4-5 mo), LTP deficit (4-6 mo), neuronal loss (4-6 mo)
5xFAD (C57BL6) [51] [52] APP, PSEN1Over-express human APP with the Swedish, Florida, and London mutations and PSEN1 with the M146L and L286V mutationsMurine Thy1LTP defecits (2 mo), Aβ plaques (2 mo), gliosis (2 mo), cognitive impairment (3-6 mo), synaptic loss (3-6 mo), neuronal loss (12 mo)
huAPOE KI [53] [54] [55] APOE2, APOE3, APOE4Express humanized APOE2, APOE3, or APOE4N/ANo data

Rat models

NameGenesModification InformationPromoterKnown Pathology (Age of Onset in Months)
McGill-R-Thy1-APP [56] APPExpress human APP with the Swedish and Indiana mutationsMurine Thy1.2Cognitive impairment (3 mo), LTP deficits (3 mo), Aβ plaques (6 mo), gliosis (6 mo), neuronal loss (18 mo), synaptic loss (20 mo)
APPNL-G-FKI [57] APPExpress humanized Aβ with the Swedish, Arctic, and Iberian mutationsN/AAβ plaques (1 mo), cognitive impairment (5-7 mo), gliosis (6 mo), synaptic loss (6 mo), neuronal loss (12 mo)
APP+PS1 [58] APP, PSEN1Express human APP with the Swedish and Indiana mutations and human PSEN1 with the L166P mutationUBCCognitive impairment (10 mo); Aβ plaques (19 mo), neuronal loss (19 mo)
TgF344-AD [59] APP, PSEN1Express human APP with the Swedish mutation and human PSEN1 with the Δexon9 mutationMurine PrPGliosis (6 mo), cognitive impairment (6 mo), Aβ plaques (6 mo), neurofibrillary tangles (16 mo), neuronal loss (16 mo)

Non-human primates

Non-human primates can be used by researchers to study mechanisms of Alzheimer's disease as well as develop therapeutics. Non-human primates are useful as they have a more similar aging pattern to humans compared to rodent models. [60] During non-human primate aging, they can display neuropathy, cognitive changes, and amyloid-β deposits, similar to that of Alzheimer's disease. [60] While these models are useful in studying the process of aging, they are not always exact models of Alzheimer's disease. Common non-human primates used in AD research include: rhesus monkeys (Macaca mulattas), stump-tailed macaques (Macaca arctoides), mouse lemurs (Microcebus murinus), the common marmoset (Callithrix jacchus), and crab-eating macaques (Macaca fascicularis). [60] These models can be studied both spontaneously or through artificial induction of Alzheimer's disease responses. [60] Common techniques used to induce these models include: cholinergic nervous system injury, amyloid-β injection, intrinsic formaldehyde, and streptozotocin (a methyl nitrosourea sugar compound which induces diabetes). [60]

Alternative organisms

Related Research Articles

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve, with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

<span class="mw-page-title-main">Neurofibrillary tangle</span> Aggregates of tau protein known as a biomarker of Alzheimers disease

Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is known about their exact relationship to the different pathologies.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Organoid</span> Miniaturized and simplified version of an organ

An organoid is a miniaturised and simplified version of an organ produced in vitro in three dimensions that mimics the key functional, structural and biological complexity of that organ. They are derived from one or a few cells from a tissue, embryonic stem cells or induced pluripotent stem cells, which can self-organize in three-dimensional culture owing to their self-renewal and differentiation capacities. The technique for growing organoids has rapidly improved since the early 2010s, and The Scientist names it as one of the biggest scientific advancements of 2013. Scientists and engineers use organoids to study development and disease in the laboratory, drug discovery and development in industry, personalized diagnostics and medicine, gene and cell therapies, tissue engineering and regenerative medicine.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">SORL1</span> Protein-coding gene in the species Homo sapiens

Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.

<span class="mw-page-title-main">TMEM106B</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.

<span class="mw-page-title-main">Early-onset Alzheimer's disease</span> Alzheimers disease developed before the age of 65

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study that aims to improve clinical trials for the prevention and treatment of Alzheimer's disease (AD). This cooperative study combines expertise and funding from the private and public sector to study subjects with AD, as well as those who may develop AD and controls with no signs of cognitive impairment. Researchers at 63 sites in the US and Canada track the progression of AD in the human brain with neuroimaging, biochemical, and genetic biological markers. This knowledge helps to find better clinical trials for the prevention and treatment of AD. ADNI has made a global impact, firstly by developing a set of standardized protocols to allow the comparison of results from multiple centers, and secondly by its data-sharing policy which makes available all at the data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, vice-chair of neurology, director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH).

<span class="mw-page-title-main">Cerebral organoid</span> Artificial miniature brain like organ

A neural, cerebral, or brain organoid, describes an artificially grown, in vitro, tissue resembling the brain. A 2022 consensus agreement is to call these neural organoids. Neural organoids are created by culturing pluripotent stem cells, which spontaneously develop into a three-dimensional culture that can be maintained for months. The brain is an extremely complex system of heterogeneous tissues and consists of a diverse array of neurons. This complexity has made studying the brain and understanding how it works a difficult task in neuroscience, especially when it comes to neurodevelopmental and neurodegenerative diseases. The purpose of creating an in vitro neurological model is to study these diseases in a more simple and less variable space. This 3D model is free of many potential in vivo limitations. The varying physiology between human and other mammalian models limits the scope of study in neurological disorders. Neural organoids are synthesized tissues that contain several types of nerve cells and have anatomical features that recapitulate regions of the nervous system. Cerebral organoids are most similar to layers of neurons called the cortex and choroid plexus. With the addition of guidance cues, other regionalized neural organoids resemble structures similar to the retina, meninges, spinal cord and hippocampus. Stem cells have the potential to grow into many different types of tissues, and their fate is dependent on many factors. Below is an image showing some of the chemical factors that can lead stem cells to differentiate into various neural tissues; a more in-depth table of generating specific organoid identity has been published since. Similar techniques are used on stem cells used to grow cerebral organoids.

The ion channel hypothesis of Alzheimer’s disease (AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of neurotoxicity seen in AD. While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of calcium ion homeostasis and subsequent apoptosis in AD, the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.

<span class="mw-page-title-main">Sergiu P. Pașca</span> Romanian-American scientist and physician at Stanford University

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<span class="mw-page-title-main">Bradlee Heckmann</span>

Bradlee L. Heckmann is an American biologist, pharmacologist. Heckmann holds academic appointments as a neuroimmunologist at the Byrd Alzheimer's Center and USF Health Neuroscience Institute and is assistant professor in molecular medicine at the USF Health Morsani College of Medicine. Heckmann's research has been focused on understanding the regulation of inflammatory and metabolic processes in the central nervous system, with particular emphasis on neurodegenerative diseases including Alzheimer's disease and the role of the autophagy machinery in this setting.

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A myelinoid or myelin organoid is a three dimensional in vitro cultured model derived from human pluripotent stem cells (hPSCs) that represents various brain regions, the spinal cord or the peripheral nervous system in early fetal human development. Myelinoids have the capacity to recapitulate aspects of brain developmental processes, microenvironments, cell to cell interaction, structural organization and cellular composition. The differentiating aspect dictating whether an organoid is deemed a cerebral organoid/brain organoid or myelinoid is the presence of myelination and compact myelin formation that is a defining feature of myelinoids. Due to the complex nature of the human brain, there is a need for model systems which can closely mimic complicated biological processes. Myelinoids provide a unique in vitro model through which myelin pathology, neurodegenerative diseases, developmental processes and therapeutic screening can be accomplished.

An assembloid is an in vitro model that combines two or more organoids, spheroids, or cultured cell types to recapitulate structural and functional properties of an organ. They are typically derived from induced pluripotent stem cells. Assembloids have been used to study cell migration, neural circuit assembly, neuro-immune interactions, metastasis, and other complex tissue processes. The term "assembloid" was coined by Sergiu P. Pașca's lab in 2017.

References

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  2. 1 2 "Dementia". www.who.int. Retrieved 2022-12-04.
  3. ↑ "10 Early Signs and Symptoms of Alzheimer's". Alzheimer's Association. Retrieved 2022-12-05.
  4. ↑ "Investing in Alzheimer's Research". alzimpact.org. Retrieved 2022-12-04.
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  34. ↑ "APPSwe (line C3-3) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  35. ↑ "Tg2576 | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  36. ↑ "APP23 | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  37. ↑ "PDAPP(line109) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  38. ↑ "TgCRND8 | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  39. ↑ "APP NL-F Knock-in | ALZFORUM". www.alzforum.org. Retrieved 2022-11-16.
  40. ↑ "APP NL-G-F Knock-in | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  41. ↑ "JNPL3(P301L) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  42. ↑ "Tau P301L | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  43. ↑ "Tau P301S (Line PS19) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-16.
  44. ↑ "008169 - Tau P301S (PS19) Strain Details". www.jax.org. Retrieved 2022-11-16.
  45. ↑ "PS1(M146V) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  46. ↑ "Tg2576/Tau(P301L) (APPSwe-Tau) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  47. ↑ "3xTg | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  48. ↑ "PS/APP | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  49. ↑ "5xFAD (B6SJL) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  50. ↑ "034840 - 5XFAD Strain Details". www.jax.org. Retrieved 2022-11-15.
  51. ↑ "5xFAD (C57BL6) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  52. ↑ "034848 - 5xFAD , 5x-FAD, Tg6799 Strain Details". www.jax.org. Retrieved 2022-11-15.
  53. ↑ "APOE2 Knock-In (JAX) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  54. ↑ "APOE3 Knock-In (JAX) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  55. ↑ "APOE4 Knock-In (JAX) | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  56. ↑ "McGill-R-Thy1-APP | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  57. ↑ "App NL-G-F Knock-in Rat | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  58. ↑ "APP+PS1 | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
  59. ↑ "TgF344-AD | ALZFORUM". www.alzforum.org. Retrieved 2022-11-15.
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