Live Discussion: The Neuroplasticity Theory of Alzheimer's Disease

Discussion text prepared by J. Wesson Ashford, MD  
Live Discussion held 8 April 2002 at 1:00pm EST

See Comments by Siegfried Hoyer

Transcript

Dr. Ashford's Bio

The most fundamental statement about Alzheimer pathology is that it attacks neuroplastic processes.  At all system levels of function (biological, psychological, social), it is the capacity to store new information that is affected by Alzheimer's disease.  Tracing memory mechanisms to their most basic levels leads to the loci at which Alzheimer pathology affects brain mechanisms.  This hypothesis was first proposed in 1985 ( Ashford & Jarvik; see Ashford, Mattson, Kumar, 1998, for full discussion).  This hypothesis has recently been rediscovered, eloquently restated, and expanded by others (see Mesulam and Arendt, 2001). This hypothesis has been supported by repeated findings that pathological mechanisms associated with Alzheimer's disease invariably end up being related to learning mechanisms (e.g., acetylcholine, norepinephrine, serotonin pathways, NMDA receptors, synapse counts, tau phosphorylation, Amyloid PreProtein, cerebral cholesterol metabolism; see Ashford, Mattson, Kumar, 1998).  

The neuroplasticity hypothesis also pulls together the tau and amyloid hypotheses with the corollary hypothesis that there are two fundamental cellular memory mechanisms, each attacked by one of  two types of pathology, the first by the amyloid (more closely linked to causation, affecting more diffuse cortical regions including the temporal and parietal lobes), resulting in senile plaques, then, once a critical point is reached, the second by tau hyperphosphorylation, which leads to the neurofibrillary pathology (correlated with dementia severity, initially affecting the hippocampus and medial temporal lobe).  In each case, if the delicate balance between forming new connections and removing connections no longer required is disrupted, Alzheimer pathology may develop.  Amyloid PreProtein processing tips away from an alpha-secretase/beta-secretase balance, to produce excess beta-amyloid and resultant free-radicals.  Tau is excessively phosphorylated to the point that it forms neurofilaments, and then neurofibrillary tangles.  The neurofilaments appear to clog dendrite segments (Ashford et al., 1998), which leads to amputation of the distal portions of dendritic trees, large scale losses of synapses, and the increase of CSF tau.  These late changes correspond with the dementia severity associated with Alzheimer's disease (Ashford et al., 2001 for a discussion of modeling of dementia severity.)

A central factor in Alzheimer's disease is ApolipoProteinE, which is produced by glial cells and accounts for at least 50% of the Alzheimer's disease that occurs between 60 - 80 years of age.  APOE plays a central role in cerebral cholesterol transport.  Recent evidence has shown that cholesterol metabolism is involved in neuroplasticity.  Epidemiological studies are now implicating cholesterol metabolism in Alzheimer causation.  This chain of causation provides yet another buttress to support the neuroplasticity hypothesis of AD.  Additional evidence suggests that cholesterol is involved in Amyloid PreProtein processing, thus linking the APOE alleles to amyloid production, thought to be central to AD causation, and further supporting the role of this mechanism in neuroplasticity and the general neuroplasticity theory of AD ( see Ashford and Mortimer debate position, in press, for full discussion and references [.pdf file]). 

Recent evidence supports the hypothesis that acetylcholine, a fundamental neurotransmitter in neuroplasticity, inhibits both senile plaque and neurofibrillary tangle formation (see figure adapted from Fisher, 2000).  This hypothesis suggests that drugs which increase acetylcholine function, such as cholinesterase inhibitors, may slow or stop Alzheimer progression.

References

Ashford, JW, Jarvik, KL. "Alzheimer's disease: does neuron plasticity predispose to axonal neurofibrillary degeneration?" New England Journal of Medicine. 5:388-389, 1985. Abstract

Ashford, JW, Mattson, M, Kumar, V. "Neurobiological Systems Disrupted by Alzheimer's Disease and Molecular Biological Theories of Vulnerability." In: Kumar, V. and Eisdorfer, C. (Eds.) Advances in the Diagnosis and Treatment of Alzheimer's Disease. Springer Publishing Company: New York, 1998. Article [.pdf file]

Ashford JW, Soultanian NS, Zhang SX, Geddes JW. "Neuropil threads are collinear with MAP2 immunostaining in neuronal dendrites of Alzheimer brain." J Neuropathol Exp Neurol 57:972-8, 1998. Abstract

Ashford, JW, Schmitt, FA. "Modeling the time-course of alzheimer dementia." Curr Psychiatry Rep. 3:20-8, 2001. Abstract

Debates on Alzheimer Theories: Cincinnati, July, 2001

• conference summary
• See Review [.pdf file] by Ashford
  
• See also a Summary [.pdf file] of debate position by Ashford and Mortimer (n press, part of the conference )

Additional References

Arendt T. "Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization." Neuroscience. 2001;102(4):723-65. Abstract

Fisher, A. "Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists." Jpn J Pharmacol. 2000 Oct;84(2):101-12. Abstract

Mesulam MM. "A plasticity-based theory of the pathogenesis of Alzheimer's disease." Ann N Y Acad Sci. 2000;924:42-52. Abstract

Comments by Siegfried Hoyer - Posted 7 April 2002

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 AbPP, Ab40 and Ab42, and reduced the intracellular concentrations of all three AbPP 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 AbPP 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 AbPP and tau protein.

Regarding AbPP, intraneuronal accumulation of Ab42 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 Ab 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 Ab. 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 post-mortem 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 Ab40 and Ab42 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 Ab concentration via inhibition of cholesterol production by statins. - Siegfried Hoyer, University of Heidelberg, Germany.