02 Aug

What glia are doing inside the Alzheimer’s brain?

The two most accepted hallmarks of Alzheimer’s disease (AD) are Amyloid-beta (Aβ) plaques in extracellular spaces, known to interfere with synapses, and intraneuronal hyperphosphorylation of Tau, a microtubule-associated protein. Since the beginning, a major focus on understanding the AD pathology has revolved around how both of these proteins affect the neuronal functioning and projected as promising targets for therapeutic intervention. However, very limited success has been achieved with drugs that were designed to target either Aβ plaques or neurofibrillary tangles. Lately, these developments have changed the course of AD research and open new avenues for its diagnostics and treatment. Researchers are now giving more emphasis on the glial cells, and this subtle change has unrevealed some significant mysteries of AD progression. So, let’s take a look at what glial cells are doing inside an AD brain.

Glial cells of the central nervous system (CNS) provide structural as well as metabolic support to the neurons. They are also involved in the maintenance of CNS homeostasis and are about 10−50 times more numerous than neurons. Astrocytes, ependymal cells, microglia, and oligodendrocytes constitute a major proportion of glial cells.


These are star-shaped cells with fine processes of variable length that differ based on their location. The major function of astrocytes is the restoration of water and ion homeostasis as well as contributing to the blood-brain barrier (BBB) maintenance (1). However, the exact role of astrocytes in the pathogenesis and progression of AD still requires thorough characterization, mainly due to a lack of human experimental data that examines the stage-dependent changes in astrocytes. Human post-mortem tissue analyses have revealed prominent reactive astrogliosis and inclusion of astrocytes into senile plaques during the late stages of AD. However, much of the understanding of their role has been based on studies with animal models. It has been observed that accumulation of Aβ could create disturbances in the Ca2+ homeostasis of astrocytes, which induce astrogliosis and cause neuroinflammation (2). Several reports have revealed that unsaturated fatty acid, e.g. palmitate, induces the NLRC4 (NLR family CARD domain-containing protein 4) expression in astrocytes and promotes AD progression (3). Interestingly, reactive astrocytes have shown to express β-secretase following occlusion of the middle cerebral artery as well as in AD mice models expressing mutant human amyloid precursor protein (APP) (4). These and several other findings have suggested that once the brain homeostasis disrupts, astrocytes can favor Alzheimer’s progression.

Ependymal cells

These cells form membrane lining of ventricles in the brain as well as the spinal cord and produce a small amount of cerebrospinal fluid, which in turn clears the accumulated Aβ from the brain during the early stages of AD (1). However, under pathological conditions, these cells have shown alteration in their lysosomal function, and instead of clearance, they promote Aβ accumulation (5). Moreover, the oxidative stress-related damage could affect the ependymal carriers (P-glycoprotein and low-density lipoprotein receptor-related protein-1) and ultimately hamper the Aβ clearance (6). In addition, these cells are also suffered from the effects of neuroinflammation, which jeopardizes the integrity of the blood-brain and the blood-CSF barrier. The pro-inflammatory molecule, nuclear factor kappa beta (NF-κB) secreted by reactive astroglia, can regulate the structural changes in ependyma, like impaired ciliary movements, which in turn affect their Aβ clearance function (7). Further, Wnt, β-catenin, and GSK-3 pathway could also alter the expression of multidrug efflux transporters and P-glycoprotein in ependymal cells, which favor the disruption of the blood-brain barrier in AD (8). A few reports have also suggested that the abundance of advanced glycation end-product receptors (RAGE) in ependymal layer could also promote the influx of glycated Aβ from blood to the brain of AD patients (9). These reports clearly show that ependymal cells play a crucial role in the clearance of Aβ from the brain.


These are the brain macrophages, derived from the hemangioblastic mesoderm, the lineage continues through myelomonocytic cells, and finally to microglia (1). Microglia constitute 5−10% of the adult brain population (10). They are uniformly dispersed at a density of 6 mm3, and each cell occupies approximately 50,000 μm3 (11). Microglial cells express triggering receptors expressed in myeloid cells 2 (TREM2) receptors, which helps in chemotaxis, phagocytosis (besides TLR4 and CD14 receptors), migration, and proliferation. However, recent reports have suggested that in Alzheimer’s, the microglial phagocytic function has been decreased due to mutations in TREM2 (12). Microglia also express CD33, SRP-β1, and TREM1 receptors. The CD33 receptor, expressed on hematopoietic as well as immune cells, belongs to a family of sialic-acid-binding immunoglobulin-like lectins. It plays an important role in the growth of immune cells, inhibition of cytokines release from monocytes, and mediates endocytosis. Reports have shown an association between increased CD33 expression and Alzheimer’s risk, as it could inhibit the microglia-mediated Aβ uptake (13). On the other hand, signal regulatory protein β1 (SRP-β1) is a DAP-12 associated transmembrane protein, expressed on macrophages, hematopoietic cells, and microglial cells. This has a major role in the clearance of Aβ fibrils through the CD 47 ligand, which is also expressed by microglia along with other brain cells. Microglial SRP-β1 expression has found to be elevated in Alzheimer’s patients. However, in aged brains, clearance of Aβ fibrils has shown to be decreased due to a dysfunctional SRP-β1/CD 47 signaling response (14). Neuronal circuits have shown to be functionally diminished at the initial stages of AD (15). Reduction in the synapse number and inhibition of LTP leads to memory decline (16). It has been shown that in an AD brain, phagocytic functions of microglia also get reduced (17). Recently, these microglial cells have been shown to attain tolerance against continuous but low doses of LPS administration (18). Therefore, it would be interesting to check whether microglia could also become tolerant to the Aβ in AD brains or not.


These cells are known as the producers of myelin, which provides electrical insulation over the axons and ensures the rapid propagation of nerve impulses. Recent findings have shown that knocking out of myelin-associated genes Ugt8, Cnp, and Plp1 resulted in myelin dysfunction and eventually neurodegeneration in the mouse. These cells have also been shown to activate inflammatory pathways in response to Aβ (3). It has been found that BACE-1 plays an important role in oligodendrocyte mediated myelin production, which was confirmed by BACE inhibitor treatment (19). It has been speculated that the breakdown of myelin may promote the accumulation of toxic Aβ fibrils that ultimately form plaques in the brain (20). Moreover, Aβ has shown to induce oligodendrocyte dysfunction by activating the neutral sphingomyelinase (nSMase) – ceramide cascade via cellular anti-oxidants (21). Glutathione (GSH) precursors have shown to attenuate nSMase mediated Aβ activation and slowed down the oligodendrocyte loss, whereas GSH scavengers can enhance the nSMase activity and Aβ-induced oligodendrocyte death. Thus, oligodendrocytes can be indirectly associated with the progression of Alzheimer’s.


Early and reliable diagnostic markers for AD are much needed right now, therefore the time has come to look into those dark areas which have not received much attention. A better understanding of the role played by glial cells in the progression of AD during the early stages would definitely be worth a shot.


  1. Verkhratsky, A., and Butt, A. (2007) Glial Neurobiology: A Textbook, John Wiley & Sons.
  2. Freeman LC, Ting JP. The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem. 2016 Jan;136 Suppl 1:29-38.
  3. Nirzhor SSR, Khan RI, Neelotpol S. The Biology of Glial Cells and Their Complex Roles in Alzheimer’s Disease: New Opportunities in Therapy. Biomolecules. 2018 Sep 10;8(3).
  4. Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR. Alzheimer’s disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem. 2005 Jan;92(2):226-34.
  5. Balusu S, Brkic M, Libert C, Vandenbroucke RE. The choroid plexus-cerebrospinal fluid interface in Alzheimer’s disease: more than just a barrier. Neural Regen Res. 2016 Apr;11(4):534-7.
  6. van Assema DM, Lubberink M, Bauer M, van der Flier WM, Schuit RC, Windhorst AD, et al. Blood-brain barrier P-glycoprotein function in Alzheimer’s disease. Brain. 2012 Jan;135(Pt 1):181-9.
  7. Lattke M, Magnutzki A, Walther P, Wirth T, Baumann B. Nuclear factor kappaB activation impairs ependymal ciliogenesis and links neuroinflammation to hydrocephalus formation. J Neurosci. 2012 Aug 22;32(34):11511-23.
  8. Liu L, Wan W, Xia S, Kalionis B, Li Y. Dysfunctional Wnt/beta-catenin signaling contributes to blood-brain barrier breakdown in Alzheimer’s disease. Neurochem Int. 2014 Sep;75:19-25.
  9. Maslinska D, Laure-Kamionowska M, Taraszewska A, Deregowski K, Maslinski S. Immunodistribution of amyloid beta protein (Abeta) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients. Folia Neuropathol. 2011;49(4):295-300.
  10. Czeh M, Gressens P, Kaindl AM. The yin and yang of microglia. Dev Neurosci. 2011;33(3-4):199-209.
  11. Lee CY, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna). 2010 Aug;117(8):949-60.
  12. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018 Feb 5;217(2):459-72.
  13. Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013 May 22;78(4):631-43.
  14. Floden AM, Combs CK. Microglia demonstrate age-dependent interaction with amyloid-beta fibrils. J Alzheimers Dis. 2011;25(2):279-93.
  15. Zott B, Busche MA, Sperling RA, Konnerth A. What Happens with the Circuit in Alzheimer’s Disease in Mice and Humans? Annu Rev Neurosci. 2018 Jul 8;41:277-97.
  16. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016 Jun;8(6):595-608.
  17. Spittau B. Aging Microglia-Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases. Front Aging Neurosci. 2017;9:194.
  18. Lelios I, Greter M. Trained Microglia Trigger Memory Loss. Immunity. 2018 May 15;48(5):849-51.
  19. McKenzie AT, Moyon S, Wang M, Katsyv I, Song WM, Zhou X, et al. Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer’s disease. Mol Neurodegener. 2017 Nov 6;12(1):82.
  20. Bartzokis G, Lu PH, Mintz J. Human brain myelination and amyloid beta deposition in Alzheimer’s disease. Alzheimers Dement. 2007 Apr;3(2):122-5.
  21. Lee JT, Xu J, Lee JM, Ku G, Han X, Yang DI, et al. Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol. 2004 Jan 5;164(1):123-31.
01 Jul

Interlaminar glia in health and disease

by Jorge A Colombo

Astroglial participation in the regulation of ionic balance, energy metabolism, morphogenesis, and neuritogenesis and synthesis of trophic factors, as well as synthesis and metabolism of neurotransmitter amino acids, confirms glial participation in multiple aspects of brain organization and function.

Although Andriezen in 1886 described glial cells with long processes in the human cerebral cortex, full morphological, developmental, and species comparative analysis was not attained until several years later. Probably due to prevalent rodent brain analysis is taken as a model to generalize their role in mammalian brain, histological, physiological, comparative, and pathological concepts -as well as their emergence during human brain development- regarding cerebral cortex astroglia were not systematically analyzed until several years later.


Albeit with variations in the density of Glia with interlaminar processes, they are present in the cerebral cortex of humans and New and Old-World monkeys, but not in the rodent (Figure 1). We proposed to label such glial morphotype as interlaminar glia due to their processes (IGP) traversing several cellular layers of the cerebral cortex.

Although the functional significance of interlaminar astroglial processes is largely unknown, it has been speculated that they represent unusually long-ranging astroglial structures that may be responsible for remote, radially organized (columnar associated) and glial-mediated influences on the neurochemical environment in the cerebral cortex. Thus, interlaminar processes may provide a different spatial configuration and dynamics for neuronal-glial interaction in the cerebral cortex, as compared to the one resulting from the conventional stellate astrocyte (Colombo et al., Anat. Embryol. 1998).

Long, glial fibrillary acid protein (GFAP)-immunoreactive (IR) astroglial processes forming ordered palisades have been characterized as a specialized feature of the primate cerebral cortex, and are most highly developed in anthropoid species (Colombo et al.,1997; Colombo et al., 1998; Colombo et al., 2000). We have previously termed these structures as “interlaminar processes” because they span several cortical layers. These specialized astrocytic processes develop postnatally [and extend downward from superficial astrocytic cell bodies, traversing the supragranular layers in a predominantly radial fashion (Colombo et al., 2002).

Alzheimer Disease

In most cortical regions of cases diagnosed as severe Alzheimer’s disease by the donor institutions, interlaminar astroglia was found to be markedly altered or absent, and replaced by hypertrophic intralaminar astrocytes.

In general, the present observations suggest that the interlaminar processes are rather labile structures compared to intralaminar processes, that they do not form part of the chronic astrocytic reactive condition, and that they may be highly dynamic structures undergoing remodeling processes upon signals from the neuropil.

Down’s Syndrome

Comparing cerebral cortex control infant cases with age matched cases with Down’s Syndrome cases, the initial organization of the IGP was similar in control and DS cases, although a breakdown in DS became manifest by the first year of age, or earlier, albeit with individual variations. These changes tended to evolve in a mosaic fashion and included partial disruption of the palisade, or persistence of the physiological astrocytosis.

As proposed earlier, the evolution of the ‘‘primate-like’’ Interlaminar Glial Palisade (IGP) in the cerebral cortex may be schematically viewed as follows: bulk of non-primate species (lack of interlaminar processes) –Chiroptera and Insectivora (scanty, isolated IGP, limited to allocortex) –Strepsirrhini (lemuriforms) (variable presence of IGP)– Haplorrhini [Platirrhini (New World\Catarrhine (Old World) (in general well-developed IGP palisade, although variable in New World species)–anthropoid species (great apes, Homo) (well-developed IGP palisade).


On speculative grounds, the presence of IGP predominant in anthropoid species could be associated with optimizing neuronal columnar organization of the primate cerebral cortex. Their progressive installation during development is probably associated with maturation of brain function. Their disruption in Alzheimer’s Disease and Down’s Syndrome cases would correlate with brain progressive dysfunction.


Andriezen WL. (1893) The neuroglia elements of the brain. Brit Med J 29:227–230.

Colombo JA, Hartig W, Lipina S, Bons N. (1998) Astroglial interlaminar processes in the cerebral cortex of prosimians and Old-World monkeys. Anat Embryol 197:369–376.

Colombo JA, Quinn B, Puissant V. (2002) Disruption of astroglial interlaminar processes in Alzheimer’s disease. Brain Res Bull 58:235–242.

Colombo JA, Reisin HD, Jones M, Bentham C. (2005) Development of interlaminar astroglial processes in the cerebral cortex of control and Down’s syndrome human cases. Exp Neurol 193:207–217.

Colombo JA.; Yáñez A; Lipina S (1997) Interlaminar astroglial processes in the cerebral cortex of nonhuman primates: Response to injury. J. Brain Res. 38:503–512.

Colombo, JA; Fuchs E.; Hartig W.; Marotte L.; Puissant V. (2000) Rodent-like and primate-like types of astroglial architecture in the adult cerebral cortex of mammals. A comparative study. Anat. Embryol. 201:111–120.

Author: Jorge A. Colombo MD, PhD
Principal Investigator (CONICET) (retired)
Buenos Aires
01 Jun

Can we delay Alzheimer’s progression?

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and primarily affects the learning and memory of an individual. A slow but gradual memory loss results in impairment of cognitive functions, which ultimately causes psychosis and dementia. AD is believed to be initiated as a result of protein aggregation, mainly by extracellular amyloid beta (Aβ) and intracellular Tau. Another aspect is the inefficient clearance of these protein aggregates from the central nervous system.

Microglia | The natural clearance system of the brain

In AD, the transformation of Aβ monomer into the soluble oligomers is considered a major event that causes actual damage to the nervous system. These soluble oligomers later transformed into a large number of insoluble fibrils and finally become plaques. Since long, microglia have been explored mostly for their neuro-inflammatory functions. However, the trend is now shifting towards their less explored functions that involve non-autonomous clearance of protein aggregates.

Whether microglia could be beneficial or detrimental to the brain, it all depends upon the type and strength of stimulus they received. It has been observed that with aging, microglia show a decline in their phagocytic behavior and could be responsible for Aβ accumulation in AD brains. But the question remains, why microglia lose their phagocytic activity in Alzheimer’s? Increasing evidence have led to an assumption that microglia could efficiently clear the Aβ and damaged neurons during the early stages of AD. However, as the disease progressed the protein aggregates clearance might be diminished due to reduced expression of several receptors as well as enzymes involved in phagocytosis and degradation of Aβ.

Microglial reprogramming

If the beneficial properties of microglia could be selectively harnessed without activating their pro-inflammatory response, a potential therapeutic strategy could be developed to check the formation of protein aggregates. To achieve this, several ways have been proposed which bank on treatment with microRNAs, cytokines, pharmacological agents, as well on nutrients supplementation. The protein aggregation usually begins in the brain silently much before any signs or symptoms are diagnosed in the patients. The major limitation in formulating any strategy against AD is to decide when we should start the treatment. Therefore, preventing or slowing down the speed of protein aggregation is more practical rather than preventing the damage caused by these aggregates.

Now the question arises, how to limit this protein aggregation and simultaneously clear whatever aggregates formed inside the brain? Although microglia efficiently take care of this in the adult brain, they lose this property in the aged AD brains. As mentioned earlier, if their phagocytic activity could be regulated then the rate of protein aggregation could also be checked. Recently, various plant derived compounds have been successfully explored as microglial modulators. The major benefit of these compounds is that they can be easily incorporated in our regular diet without any side effects, something which is missing from the existing marketed drugs for AD.

Sulforaphane | The microglia reprogrammer?

A recently explored compound is Sulforaphane (SFN), an isothiocyanate, which is present in the cruciferous vegetables like cabbage, brussel sprouts, cauliflower, and mostly in broccoli sprouts. SFN has shown to activate Nrf2 mediated antioxidant response pathway and also induce macrophages phagocytic activity. These properties make SFN as an attractive candidate to modulate microglia. Recently, our group has shown that SFN administration could prevent microglial phenotype switching when exposed with toxic amyloid oligomers. In addition, SFN treated microglia has shown a slight increase in their phagocytic activity and thereby successfully engulfed the Aβ oligomers in vitro. Previously, we have shown that SFN could improve the learning and memory of rodents if administered during their postnatal brain development. Taken together, our findings along with other reports have indicated that the inclusion of SFN in the diet may increase the chance of slowing down the progression of Alzheimer’s and other proteinopathies. Currently, we are involved in the further tweaking of SFN mediated microglial phenotype switching and trying to enhance their Aβ clearance function without activating the pro-inflammatory response in the aged rodent AD model.

Take home message: Add broccoli sprouts and other cruciferous vegetables in your diet.

Important Links

More about Alzheimer’s disease

Alzheimer’s facts and figures