The Neuroplasticity Theory of Alzheimer's Disease - AlzForum Alzheimer Research Live Discussions

On Insulin and Neuronal Plasticity
Functionally, synaptic plasticity forms the most important site of neuronal plasticiy. Recent evidence suggests that both activity and plasticity of synapses depend on biochemical stimuli induced by the expression of the activity-regulated cytoskeleton-associated gene (ARC), which is regulated by the insulin/insulin receptor signal transduction cascade (Steward et al, 1998; Zhao et al, 1999; Guzowski et al, 2000; Park, 2001; Kremerskothen et al, 2001). Oxidative glucose metabolism, including ATP-production and acetylcholine formation in the brain, are controlled by insulin acting in the brain (for review see Hoyer, 2000a).

Recent findings indicate that AbPP trafficking is under the control of insulin and the insulin receptor tyrosine kinase. Insulin increased dose-dependently the extracellular levels of AβPP, Aβ40 and Aβ42, and reduced the intracellular concentrations of all three AβPP derivatives (Solano et al, 2000; Gasparini et al, 2001). In all probability, cell cycle-associated enzymes and, consequently, cell cycle function in the brain, are under control of the insulin/insulin receptor (Conejo and Lorenzo, 2001; Conejo et al, 2001).

Figure 1 summarizes the normal function of the neuronal insulin/insulin receptor (I/IR)

activation of oxidative energy metabolism
maintains endoplasmatic reticulum (ER) / Golgi apparatus (GA) in maintaining a pH of 6
activation of the S/G2/M phases of the cell cycle
regulation of normal metabolism of both AβPP and tau protein (for review see Hoyer, 2000).

In sporadic Alzheimer's brain, both insulin concentration and activity of the insulin receptor tyrosine kinase are reduced. However, the density of the insulin receptor increases, indicating its upregulation and desensitization, similar to what happens in type II diabetes (Frohlich et al, 1998; Hoyer, 1998). As a consequence, a cascade of cellular and molecular abnormalities is set in motion, as summarized in Figure 2:

the decrease in oxidative energy metabolism causes a deficit of ATP (Hoyer, 1992), which affects the ER/GA and protein trafficking (Verde et al, 1995),
inhibition of the S/G2/M phases and activation of the G1-phase of the cell cycle (see above); a recent study on Alzheimer patients confirms signs of a G1 regulatory failure in lymphocytes (Nagy et al, 2002).
abnormal metabolism of AβPP and tau protein.

Regarding AβPP, intraneuronal accumulation of Aβ42 leads to reduced concentrations in CSF (Tapiola et al, 2000), intracellular Ab42 is assumed to play a direct pathogenetic role in sporadic AD (Gouras et al, 2000). Tau, on the other hand, becomes hyperphosphorylated in ATP-deficient conditions (Röder and Ingram, 1991; Mandelkow et al., 1992; Bush et al, 1995).

In conclusion, the above data indicate that the amyloid cascade hypothesis is not valid for sporadic Alzheimer's disease, nor for disturbed neuroplasticity. Instead, we think the latter is initiated largely by a dysregulation of the neuronal insulin receptor.

On Cholesterol in AD
Intense discussion on the relationship between cholesterol and Aβ followed the publication of two retrospective clinical studies on a mixed dementia population (vascular dementia, sporadic Alzheimer dementia, secondary dementias) treated with statins (Jick et al, 2000; Wolozin et al, 2000) since the prevalence of dementia was reduced after treatment. Studies in cultured fetal hippocampal neurons and healthy adult guinea pigs, both treated with a statin in inadequately high dosages, resulted in a reduced formation of Aβ. T??? was interpreted as being beneficial for Alzheimer's disease (Simons et al, 1998).

Cholesterol is an essential sterol constituent of membranes and guarantees and stabilizes their function and structure. The neuron's capacity to form synapses depends on the availability of cholesterol, which is mainly provided by glia cells (see ARF news story). Intracellulary, cholesterol is formed from acetyl-CoA. Inhibition of its production decreased dendritic outgrowth and induced cell death (Michikawa and Yanagisawa, 1999; Fan et al., 2002).

Membranes in Alzheimer brains are severely damaged in their liquid composition, including cholesterol, which was demonstrated to be reduced in different brain areas (Svennerholm and Gottfries, 1994).

In postmortem Alzheimer brains, the unesterified cholesterol:phospholipid mole ratio decreased by 30 percent in the temporal gyrus. This lower membrane cholesterol content is assumed to cause an average 4A° (Angström) reduction in the lipid bilayer width, altering the biophysical properties of such damaged membranes (Mason et al, 1992). The reduction of cholesterol's cellular formation and membrane concentration in Alzheimer brains is mirrored by a decrease of cholesterol concentration in CSF (Mulder et al, Alzheimer Dis Ass Disord 1998; 12: 198-203). Destruction of cholesterol-rich cell membranes leads to a release of cholesterol from the brain in form of its derivative 24S-hydroxycholesterol in plasma and mainly in CSF (Lütjohann et al, 2000; Papassotiropoulos et al, 2002). This enhanced cholesterol efflux from the brain might follow an abnormal induction of the cholesterol-catabolic enzyme CYP 46 in glial cells (Bogdanovic 2001). Since both Aβ40 and Aβ42 concentrations are reduced in the CSF during the spontaneus course of Alzheimer patients, and both cholesterol formation and concentration in Alzheimer brain are reduced in the disease process, there is no rational for a therapeutic strategy to reduce Aβ concentration via inhibition of cholesterol production by statins.

View all comments by Siegfried Hoyer