Amyloid Beta and fibrillogenesis

Overview Topics

There is some controversy in this area, so that parameter values are difficult to identify conclusively.

The authors of [1], [2] investigated the formation of amyloid fibers and assumed that

A nucleation step is needed
Nuclei are produced from seeds and from micelles
Fiber elongation occurs by irreversible binding of monomers to fiber ends.

In their kinetic theory for fibrillogenesis (similar to growth of actin fibers, but irreversible) , they find a critical concentration of monomers, C* which is required for fiber elongation.

Parameter and meaning	Value suggested in literature	Reference
k_n = number of nuclei produced by 1 micelle per unit time	2.4 x 10 ^-6 / sec	[1], [2]
K_e = (number of monomers attached per unit time to 1 fibril) / ( concentration of free A-beta monomers)	90 / M /sec	[1], [2]
C* = critical concentration of monomers for fiber growth	0.1 mM (remark: probably not relevant for in vivo conditions; seems too high)	[1], [2]
G = growth rate	0.5 monomers/ min on each fibril	[1], [2]
M_o = Typical micelle aggregation number	10	[1], [2]
Typical fraction of protein in seed form	1 %	[1], [2]
v = Amyloid Beta fiber elongation rate	v=5 + 0.25[A-Beta]	[3]
[A-Beta] = typical concentrations used in experiments	25 microM - 1.7 mM 0 - 200 microM	[1], [2] [3]
Longest Amyloid Beta fiber (in vitro)	200 nm	[3]
Average length of Amyloid Beta fiber (in vitro)	15 - 30 nm	[3]
Amyloid Beta critical concentration estimates reached in experiments	10 - 40 microM	[3]
[Cu²⁺] = concentration in synaptic cleft	15 microM	[4]
[Cu²⁺] = concentration in normal cortex	100 microM	[4]
[Cu²⁺], [Fe³⁺], [Zn²⁺] = concentrations in amygdala of AD* brain	300, 700, 790 microM	[4]
[Cu²⁺], [Fe³⁺], [Zn²⁺] = concentrations in senile plaques	400, 950, 1100 microM	[4]
Amyloid Beta aggregates in the presence of Cu²⁺	[A-Beta] = 20 nM [Cu²⁺] < 1 microM	[4]
Amyloid Beta aggregates in the presence of Zn²⁺	[A-Beta] = 15.9 microM [Zn²⁺] = 25 microM	[5]
Lowest concentration at which [A-Beta] forms Zn²⁺-induced aggregates	[A-Beta] < 0.8 microM [Zn²⁺] = 25 microM	[5]
Final concentration of [A-Beta] in Zn²⁺-induced aggregates	[A-Beta] = 1.6 microM	[5]
Size estimation of Amyloid Beta aggregates (in vitro)	> 0.1 microM, 47% > 0.22 microM, 40% > 0.65 microM, 32%	[5]
Size estimation of Zn²⁺-induced Amyloid Beta aggregates (in vitro)	> 0.1 microM, 95% > 0.22 microM,92% > 0.65 microM, 82%	[5]
K_d = k- / k+	k- = unbinding parameter k+ = binding parameter
K_d = Zn²⁺ binding to Amyloid Beta (low affinity)	5.2 microM	[5]
K_d = Zn²⁺ binding to Amyloid Beta (high affinity)	107 nM	[5]
[Zn²⁺] = extracellular concentration levels in hippocampus	0.15 - 100 microM	[5]
Total Amyloid Beta concentration in individuals with AD*	8.8 microM	[6]
Total Amyloid Beta concentration in Control individuals	0.6 microM	[6]

*AD=Alzheimer's Disease

Remarks

According to [3], and unlike [1] and [2], growth of fibrils was a linear function of A beta concentration, with 10 nm/h at 32 microM and 45 nm/h at 160 microM (i.e. with slope 0.27 nm/h per microM). Estimates of the critical concentrations were at first suggested to be , 10-40 microM, but later found to be lower, e.g. 8-9 microM. Disassembly was observed at -24 nm/day at 8 microM. Average length of fibrils was 14-30 nm, and the longest fibrils were 86- 177 nm.
According to [4], concentration levels of Cu²⁺, Fe³⁺, and Zn²⁺ are significantly elevated within AD neuropil compared with control neuropil. Furthermore, these metal ions have significantly higher concentrations within the core and periphery of plaque deposits.
The kinetics of Amyloid Beta aggregation in the presence of Zn²⁺ are as follows: (see [5]). There are two phases observed over 2 hours. Initial phase is rapid, with half-maximal assembly rate of ~0.4 microM / min. The second phase has aggregation rate of 3.2 microM / min.

References

[1] Lomakin A, Teplow D B, Kirschner D A, Benedek G B (1997). Kinetic theory of fibrillogenesis of amyloid beta protein. Proc. Natl. Acad Sci. USA 94: 7942-7947.
Abstract

[2] Teplow D (1998). The biophysics of amyloid beta protein fibrillogenesis. in: C Haass, ed.; Molecular Biology of Alzheimer's disease: genes and mechanisms involved in amyloid generation, Harwood, Canada.

[3] Harper J D, Wong S S, Lieber C M, Lansbury P T Jr (1999). Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease. Biochem 38: 8972-8980.
Abstract

[4] Atwood Craig S. Moir Robert D. Huang Xudong. Scarpa Richard C. Bacarra N Michael E. Romano Donna M. Hartshorn Mariana A. Tanzi Rudolph E. Bush Ashley I. Dramatic aggregation of Alzheimer Abeta by Cu(II) is induced by conditions representing physiological acidosis. Journal of Biological Chemistry. 273(21). May 22, 1998. 12817-12826.
Abstract

[5] Bush Ashley I. Pettingell Warren H. Multhaup Gerd. Paradis Marc D. Vonsattel Jean-Paul. Gusella James F. Beyreuther Konrad. Masters Colin L. Tanzi Rudolph E. Rapid induction of Alzheimer A-beta amyloid formation by zinc. Source Science (Washington D C). 265(5177). 1994. 1464-1467.
Abstract

[6] Cherny Robert A. Legg Jacinta T. McLean Catriona A. Fairlie David P. Huang Xudong. Atwood Craig S. Beyreuther Konrad. Tanzi Rudolph E. Masters Colin L. Bush Ashley I. Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion. Journal of Biological Chemistry. 274(33). Aug. 13, 1999. 23223-23228.
Abstract

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