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The Lee-Benner Theory
on a Cause of Alzheimer's Disease [AD] :


E-Newsletter No. 60

I formulated this theory and published it as a chapter on the aging brain in my textbook, Physician's Guide to Aging, the Immune System and Free Radical Damage, in 1984. In my effort to find a treatment for senile dementia of the Alzheimer's type, I had become intrigued with the concept of the origin of the neurofibrillary tangles and neuritic plaques that are the hallmark of the disease. The short double helical strands of protein in the neurofibrillary tangles are biochemically and immunologically unlike neurofilaments of healthy neurons. The paired helical filaments consist of uniform 10 nm in diameter filaments, wound in a helix with a half turn period of approximately 80 nm, and lacking the side arms found in normal neurofilaments. Neurons can be artificially degenerated by injecting aluminum salts into the brain. This results in large numbers of 10 nm single filaments that resemble normal neurofilaments, but not paired helical filaments. The amyloid that is found in the plaques was reminiscent to me of amyloid deposits found in the brains of aging Down's syndrome cases, as well as that occurring in other sites of the body associated with aging.

Double helical strands of protein [spectrin polymers] form the cytoskeleton of the red cell membrane. Amyloid is a secretory product from peripheral blood macrophages. I asked myself; could there be a mechanism whereby these two substances were linked, and could they invade the brain together to possibly cause the hallmark of this disease?

Thirty-four years ago, it was generally believed that the blood-brain barrier [BBB] was impenetrable to antibodies, which are produced by B-cells, and, therefore, would not be subject to immunological attack from outside the central nervous system [CNS]. On the other hand, T-cells [lymphocytes] are easily sensitized to neuroantigens [the weak tolerance to neuroantigens can be easily disrupted]. T-cells were known to cause the immunologic injury of Experimental Allergic Encephalomyelitis. T-cells, known as activated cytotoxic lymphocytes, were implicated as the cause of Multiple Sclerosis. In addition, AIDS-related dementia was being hypothesized as an autoimmune attack from HIV-infected T-cells migrating across the BBB. A subset of T-cells, [T-8] suppressor T-cells, distinct from the T-cells [T-4] that function as helpers of B-cells in the antibody response, were known to be responsible for tolerance to antigenic challenge. With aging, there is a gradual decline in immune function known as immunesenescence. This is due to a global decline in B-cell antibody production, and in addition, there is a decline in helper T-4 cell activity, and an increase in suppressor T-8 cell activity. Thus, even normal aging alters the body's innate self-recognition defense which guards it against attacking itself [an autoimmune attack].

Although, at the time that I formulated my theory, there was a paucity of supporting evidence, it was my belief that two corresponding events had to occur, one in the CNS, in order to facilitate the attraction of T-cells to invade the blood brain barrier, and one in the peripheral blood system. This occurs in stages. The first stage is inflammation from the production of reactive oxygen species [free radicals] to damage aging synaptic membranes, axons, and stimulate production of chemoattractants within the CNS, altering the BBB's permeability. The second stage occurs when reactive oxygen species cause oxidation of the aging red blood cell membrane, resulting in lysis and fragmentation of the particles. These fragmented particles are then partially phagocytized by peripheral blood macrophages, to be presented as antigens to the T-cells. This causes the T-cells to become activated to the spectrin polymers as antigens. The T-cell must undergo a 7 to 14 day period of maturation before it can become activated. This is known as a delayed hypersensitivity reaction.

I hypothesized that the third stage is when peripheral blood macrophages containing the spectrin polymers link and migrate together with the activated T-cells to cross the BBB. Both the RBC membrane and the axon contain spectrin polymers and acetylcholine precursors which are antigenically similar, and may explain the source of the antigenic response targeting the neurites. [Tubulin may be a further degradation product]. The peripheral blood macrophage secretes amyloid, and disintegrates, depositing the double helical strands of spectrin polymers in the CNS. Amyloid is believed to be initially a nerve growth factor, but after it accumulates, it is considered to be a neurotoxin, which, I thought, may explain the role of amyloid in plaque formation. Recently, treatment has been attempted to reverse amyloid plaque formation in a clinical trial using a monoclonal antibody targeting cerebral amyloid, but it had to be abandoned because of unacceptable toxic side effects.

In essence, what is proposed is that the brain is highly vulnerable to inflammation. The mechanism in the CNS is a function of free radical damage which has a greater effect in the CNS than anywhere else in the body, because neurons do not reproduce themselves, and because they are surrounded by highly peroxidizable fatty acids. The CNS has a very high content of docosahexanoic acid [DHA], which is a highly unsaturated, readily peroxidized fatty acid. There is more of it in the brains of females than in males, which may explain why the incidence of AD is apparently more prevalent in females than it is in males.

The synaptic-rich areas of the brain are vulnerable to this peroxidation, particularly the memory center and its pathways. Just as oxidant stress causes the aging red cell membrane to lose its flexibility and rupture in the peripheral blood circulation, in the CNS, it causes oxidative damage to aging neurons. Oxidation of DHA results in an arachidonic [fatty acids] cascade of prostaglandins and leukotrienes producing reactive oxygen species, causing oxidation at the synaptic membrane and axons, as well as, activation of mature dendritic cells to release inflammatory chemokines, causing further inflammation. We now know from cardiovascular studies there is an inflammatory response that promotes activation and migration of T cells and macrophages from the peripheral blood circulation causing vascular wall inflammation. The specific mediators of vascular inflammation and their mechanisms of action are still not well understood. However, mechanisms in the CNS are probably similar, that is, activated dendritic cells in the CNS, as in the vascular wall, probably also express receptors and release inflammatory cytokines [IL-6 and IL-18] that promote activation of T cells and vascular inflammation within the CNS. IL-18 up-regulates the release of interferon [INF] gamma from T cells. INF gamma released from activated T cells promotes inflammation, granuloma formation, and macrophage activation and differentiation. Activated macrophages from the CNS produce a variety of mediators that lead to progressive inflammation, releasing cytokines [IL-1, IL-6], and, more importantly, amyloid.

There is a great deal more supportive data, along with annotated references, regarding this hypothesis in my textbook. However, including all the extensive details leading to my conclusions goes beyond the scope of this newsletter. Suffice it to say, AD, in my opinion, is an inflammatory, autoimmune disorder, brought on by a combination of factors: immune decline associated with aging; accumulative effects of free radical damage; and, a delayed hypersensitivity reaction. In addition, AD may be better characterized as a form of localized amyloidosis, and be more appropriately renamed as:" Cerebral Amyloidosis." Also, in the future, treatment may be more effective, if we focus on prevention and intervention, rather than on reversal.


Lord Lee-Benner, MD, FACE

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