Critical role of intraneuronal Aβ in Alzheimer's disease: technical challenges in studying intracellular Aβ.
OBJECTIVE
Multiple lines of evidence have implicated β-amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD). However, the mechanism(s) whereby Aβ is involved in the disease process remains unclear. The dominant hypothesis in AD has been that Aβ initiates the disease via toxicity from secreted, extracellular Aβ aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of Aβ that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal Aβ has been of major interest in the field, technical difficulties in detecting intraneuronal Aβ have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal Aβ in AD and provide insights both into challenges faced in detecting intracellular Aβ and the prion-like properties of Aβ.


METHODS
Immunoprecipitation and Western blot are used for Aβ detection.


RESULTS
We highlight that a standard biochemical method can underestimate intraneuronal Aβ and that extracellular Aβ can up-regulate intracellular Aβ. We also show that detergent can remove intraneuronal Aβ.


CONCLUSIONS
There is a growing awareness that intraneuronal Aβ is a key pathogenic pool of Aβ involved in causing synapse dysfunction. Difficulties in detecting intraneuronal Aβ are an insufficient reason for ignoring this critical pool of Aβ.
Experimental Dementia Research Unit, BMC-B12, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Sölvegatan 19, 221 84 Lund, Sweden. gunnar.gouras@med.lu.se
Gunnar K
GK
Gouras
Katarina
K
Willén
Davide
D
Tampellini
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D017830:Octoxynol; D012503:Saponins; D014357:Trypsin
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047908:Intracellular Signaling Peptides and Proteins; D012503:Saponins; D017830:Octoxynol; D014357:Trypsin