The amyloid beta ion channel hypothesis of Alzheimer’s disease

Figures & data

Figure 1 APP proteolytic processing and major fates of the amyloid β (Aβ) fragment. Sequential cleavage by β-secretase (BACE-1) followed by γ-secretase [containing Presenilin 1 and 2 (PS1/2)] generates Aβ. This fragment has several fates. (a) It can aggregate and accumulate as extraneuronal plaques which characterize Alzheimer’s dementia. (b) It can be cleared from the extracellular space (a mechanism that may be altered in AD brains). (c) It can be degraded by a variety of proteases such as Insulin Degrading Enzyme (IDE), Neprilyisn (NEP), Plasmin, Plasminogen Activator (uPA/tPA), Endothelin Enzyme-1 or Matrix Metalloprotease-9 (MMP-9). Hypothetically, at least, it might return to the plasma membrane and insert in oligomer form as an ion channel. γ-secretase cleavage is also thought to liberate an intracellular domain (AICD) which may influence gene transcription.

Figure 2 Sequential cleavage by β-secretase and γ-secretase releases Aβ fragment of varying length. β-secretase cleavage has to occur following internalization of APP-enzyme complex at pH values around 4.0 in cytosolic locations.

Figure 3 APP internalization and generation of Aβ. APP is trafficked through constitutive secretory pathways, undergoes post-translational modification and ultimately locates to the plasma membrane. Poorly understood mechanisms/signals then effect internalization/endocytosis of APP to intracellular sites where optimum pH exists for activation of is β-secretase (BACE-1) that process APP.

Table 1 Summary of native neuronal ion channels

Voltage-gated Ca^2+ channels on the cell surface (VOCCs)	These channels are one of the two main routes of Ca^2+ entry into the cell and are regulated by changes in membrane voltage (Hofmann et al 1994; Hollmann and Heinemann 1994; Catterall 1998).
Ionotropic Ca^2+ channels	This is the other main variety of Ca^2+ channels expressed on the neuronal membrane and are gated by binding of specific agonists (eg, ATP) (Gever et al 2006).
Intracellular Ca^2+ channels	This class of Ca^2+ channels is found on the membranes of intracellular Ca^2+ stores, ie, endoplasmic reticulum (ER) (Furuichi and Mikoshiba 1995; Verkhratsky and Shmigol 1996).

Table 2 Summary of selected key publications which support, directly or indirectly, the ion channel hypothesis of AD pathogenesis. Note relative dominance of in vitro systems and that the majority of studies utilized exogenous Amyloid β_1–40

Citation	Experimental system	Aβ species	Main conclusions
Arispe, Rojas and Pollard, PNAS, 1993	Artificial membranes	1–40	Cation selective channel formation by exogenous Aβ 1, 40 application, recording of Ca^2+ currents and blockade of these by Tromethamine and Al^3+.
Whitson and Appel Neurobiol Aging, 1995	Rat Hippocampal neuronal culture	1–40	Neuronal survival assessed following exposure to exogenous Aβ1, 40. Diltiazem (Ca^2+ channel blocker) attenuated toxicity of Aβ while other blockers did not.
Sanderson, Butler and Ingram, Brain Res, 1997	hNT Human teratocar cinoma (neuron-like) immortalized cell line	25–35	hNT cells displayed inward Ca^2+ currents with exposure to μM concentrations of Aβ 25, 35.
Kawahara, Arispe, Kuroda et al Biophys, J 1997	Immortalized hypothalamic neurons (GT1–7)	1–40	Formation of cation channels were seen after application of Aβ1, 40. Zn^2+ blocked these channel currents
Rhee, Quist and Lal, J Biol Chem, 1998	Synthesized liposomes with Aβ1, 42 incorporated	1, 42	Large influx of Ca^2+ seen in liposomes constituted with Aβ1, 42. Effect was blocked by Tris and Zn^2+.
Hirakura, Lin and Kagan, J Neurosci Res, 1999	Planar lipid bilayers	1–42 and 1–40	Both species induced currents which were cation selective and were blocked by Zn^2+ and Congo Red.
Lin, Bhatia and Lal, FASEB J, 2001	Planar lipid bilayers	1–42	Atomic Force Microscopic (AFM) evidence of multimeric structures formed in planar lipid bilayers under the influence of Aβ1–42. Aβ1–42 induced neuritic degeneration and neuronal death and these effects were blocked by Zn^2+.
Arispe, J Memb Biol, 2004	Planar lipid bilayers	1–40	Cation-selectivity observed in ionic currents recorded from lipid bilayers were blocked by custom made peptides designed to block the putative channel pore.
Quist, Duodevski, Lin et al PNAS, 2005	Planar lipid bilayers	1–40	Aβ 1–40 induced ionic currents in planar lipid bilayers. AFM evidence for channel-like structures in these structures when exposed to Aβ1–40.

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