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The Lee-Benner Theory on a Cause of Alzheimer's Disease [AD] : THE RED CELL HYPOTHESIS |
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.
Sincerely,
Lord Lee-Benner, MD, FACE
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