Poor Digestion in Alzheimer’s Microglia: Is Beclin to Blame?

Microglia in the Alzheimer’s brain struggle mightily to devour Aβ deposits. Now, in the September 4 Neuron, researchers led by Tony Wyss-Coray at Stanford University, California, report that beclin 1, a protein whose levels are down in microglia of the AD brain, plays a key role in revving up phagocytosis. Beclin promotes the trafficking of receptors that bind to extracellular waste such as Aβ, the authors found. Without it, microglia phagocytose unenthusiastically. The findings could point to new therapeutic targets for restoring phagocytosis and improving Aβ clearance, suggest the authors.

Other researchers expressed enthusiasm for the paper, noting that it dovetails nicely with recent genetic results. Variants of the microglial receptors Trem2 and CD33 that dampen phagocytosis are associated with a higher risk of AD (see ARF related news story; ARF related news story;). Other phagocytic receptors, such as FcγRIIb and CD36, have also been linked to Alzheimer’s pathogenesis (see ARF related news story; ARF related news story;). Microglia form part of the innate immune system and perform most immune functions in the brain. “Innate immunity has taken center stage in AD [research],” said Terrence Town at the University of Southern California, Los Angeles.

Previously, beclin 1 was chiefly known for promoting a cellular waste disposal system called autophagy. In 2008, Wyss-Coray and colleagues showed that beclin 1 levels drop in the entorhinal cortex of AD brains, and that neurons deficient in beclin 1 develop large lysosomes and accumulate more Aβ. Presumably, this is because without efficient autophagy, amyloid precursor protein (APP) accumulates, allowing it to be snipped into Aβ. In line with this, the researchers showed that pumping up beclin 1 in transgenic AD mice lowered Aβ deposits by half (see ARF related news story; Spencer et al., 2009 ).

Beclin may participate in other processes besides autophagy, however. Researchers think this is so because beclin 1 knockout mice die in utero, while knockouts of other autophagic proteins survive. Some previous studies hinted that beclin 1 might be involved in phagocytosis. The protein migrates to vesicles where phagocytosis takes place, and cells lacking beclin 1 have trouble clearing extracellular debris (see Sanjuan et al., 2007; Berger et al., 2010; Qu et al., 2007).

To directly investigate whether beclin 1 contributes to phagocytosis, first author Kurt Lucin knocked down the protein in cultured microglial cells. Compared to control cells, these microglia choked phagocytosing fluorescent beads. Similarly, microglia isolated from beclin 1 heterozygous knockout mice had trouble with this task. Intriguingly, the beclin-deficient cells readily swallowed one bead, but then got stuck, unable to continue eating. The authors wondered if inefficient recycling of phagocytic receptors might be to blame. Normally, after receptors bind extracellular debris and are internalized, they are returned to the cell surface to be used again. However, in beclin-deficient microglia, phagocytic receptors such as CD36 and Trem2 did not reappear on the cell surface, the authors found.

Why might this be? A protein complex known as the retromer facilitates the intracellular transport of receptors. Microglia with low beclin levels contained little retromer, but overexpressing the retromer protein Vps35 improved their receptor recycling and phagocytosis. Beclin 1 may regulate the retromer complex, the authors thought. Beclin 1 did not directly interact with Vps35. Instead, the authors found that a complex of beclin 1 and the kinase Vps34 modified lipids in vesicles, allowing the retromer complex to bind them. In microglia with little beclin, less retromer was recruited to vesicles, receptors stalled, and phagocytosis faltered. Intriguingly, retromers have been genetically linked to Alzheimer’s and Parkinson’s in numerous studies (see, e.g., ARF related news story; ARF related news story; ARF related news story; ARF related news story).

The authors then tied the findings to AD, first showing that microglia lacking beclin poorly digested Aβ deposits when added to brain slices from aged APP transgenic mice. Restoring beclin levels rescued phagocytosis. Likewise, when the authors injected fibrillar Aβ into the frontal cortex of beclin 1 heterozygous knockouts, twice as much Aβ remained after 48 hours as in wild-type littermates. Beclin heterozygotes crossed with APP transgenic mice also accumulate more Aβ than normal transgenics, Wyss-Coray told Alzforum.

Do these findings translate to people? As a first stab at this question, the authors report that microglia isolated from AD brains had only half as much Vps35 and about 10 percent as much beclin 1 as those from age-matched controls. In future work, Wyss-Coray will investigate why beclin falls in AD brains. It is not simply a result of amyloid pathology, as the protein stays high in transgenic mice that overexpress APP, he noted. Previous studies have shown that microglia in both AD brains and AD mouse models poorly phagocytose Aβ deposits (see, e.g., ARF related news story; Feng et al., 2011).

Scott Small at Columbia University, New York City, said the data suggest that beclin 1 may play a dual role in protecting against Alzheimer’s, retarding A production by neurons and improving clearance by microglia. Both processes might contribute to the greater amyloid pathology seen in beclin heterozygotes, Small suggested. Currently, Wyss-Coray is making beclin 1 conditional knockout mice, which will allow him to disentangle the effects of losing the protein only in microglia or only in neurons. Small pointed out that the paper brings together three of the main mechanisms that have been genetically linked to AD: phagocytosis, endosomal trafficking, and lipid biology. “This cell biology data shows that all those factors can interact in one pathway,” he told Alzforum.

The data imply that turning up beclin 1 expression could help prevent AD, but researchers agreed that beclin itself would be difficult to target therapeutically. This protein is found in most cells and performs many jobs, including its crucial role in autophagy. Proteins that interact with beclin, such as the kinase Vps34, might turn out to be better targets, Wyss-Coray suggested. While therapeutic possibilities remain hazy, commentators expressed excitement over the picture that is emerging. “This paper drives home the point that microglial regulation affects AD risk,” said Steve Estus at the University of Kentucky, Lexington.—Madolyn Bowman Rogers.

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References

News Citations

  1. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  2. Protective Microglial Gene Variant Promotes Phagocytosis
  3. Immune Cell Receptor Gives Aβ a Toxic Edge
  4. Scavenger Receptor Regulates Inflammasome Activation, IL-1β
  5. Autophagy Regulator Helps Neurons Stomach Excess Aβ, Resist AD
  6. Mice, Flies Further Implicate Retromer in AD Pathogenesis
  7. APP Sorting Protein May Link Alzheimer’s and Diabetes
  8. Sorting Out Parkinson’s: Exome Sequencing Points to Recycling Defect
  9. Coming Into Vogue? Retromer in APP Processing, AD Pathogenesis
  10. Popcorn Plaque? Alzheimer Disease Is Slow, Yet Plaque Growth Is Fast

Paper Citations

  1. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci. 2009 Oct 28;29(43):13578-88. PubMed.
  2. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature. 2007 Dec 20;450(7173):1253-7. PubMed.
  3. Berger SB, Romero X, Ma C, Wang G, Faubion WA, Liao G, Compeer E, Keszei M, Rameh L, Wang N, Boes M, Regueiro JR, Reinecker HC, Terhorst C. SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages. Nat Immunol. 2010 Oct;11(10):920-7. PubMed.
  4. Qu X, Zou Z, Sun Q, Luby-Phelps K, Cheng P, Hogan RN, Gilpin C, Levine B. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell. 2007 Mar 9;128(5):931-46. PubMed.
  5. Feng Y, Li L, Sun XH. Monocytes and Alzheimer's disease. Neurosci Bull. 2011 Apr;27(2):115-22. PubMed.

Further Reading

Primary Papers

  1. Lucin KM, O'Brien CE, Bieri G, Czirr E, Mosher KI, Abbey RJ, Mastroeni DF, Rogers J, Spencer B, Masliah E, Wyss-Coray T. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron. 2013 Sep 4;79(5):873-86. PubMed.

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